Substituted anilino-quinazoline (or quinoline) compounds and use thereof

ABSTRACT

The invention concerns amide derivatives of Formula (I), wherein: G is N or CH; R 1  is a group such as hydroxy, halo, trifluoromethyl, C 1-6 alkyl and C 1-6 alkoxy; each of R 2  and R 3  is hydrogen, halo, C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl; R 4  is a group such as hydrogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy and C 3-7 cycloalkyl, or R 4  is of the Formula (IC): —K—J, wherein J is aryl, heteroaryl or heterocyclyl and K is a bond or a group such as oxy and imino, R 5  is a group such as hydrogen, halo and trifluoromethyl: m is 1-3 and q is 0-4; or pharmaceutically acceptable salts or in vivo cleavable esters thereof; processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of diseases or medical conditions mediated by cytokines.

This application is the national phase of international applicationPCT/GB99/03220 filed Sep. 27, 1999 which designated the U.S. and thatapplication was published under PCT Article 21(2) in English.

This invention concerns certain amide derivatives and their use asinhibitors of cytokine mediated disease. The invention also concernsprocesses for the manufacture of said novel amide derivatives,pharmaceutical compositions containing them and their use in therapeuticmethods, for example by virtue of inhibition of cytokine mediateddisease.

The amide derivatives disclosed in the present invention are inhibitorsof the production of cytokines such as Tumour Necrosis Factor(hereinafter TNF), for example TNFα, and various members of theinterleukin (hereinafter IL) family, for example IL-1, IL-6 and IL-8.Accordingly the compounds of the invention will be useful in thetreatment of diseases or medical conditions in which excessiveproduction of cytokines occurs, for example excessive production of TNFαor IL-1. It is known that cytokines are produced by a wide variety ofcells such as monocytes and macrophages and that they give rise to avariety of physiological effects which are believed to be important indisease or medical conditions such as inflammation and immunoregulation.For example, TNFα and IL-1 have been implicated in the cell signallingcascade which is believed to contribute to the pathology of diseasestates such as inflammatory and allergic diseases and cytokine-inducedtoxicity. It is also known that, in certain cellular systems, TNFαproduction precedes and mediates the production of other cytokines suchas IL-1.

Abnormal levels of cytokines have also been implicated in, for example,the production of physiologically-active eicosanoids such as theprostaglandins and leukotrienes, the stimulation of the release ofproteolytic enzymes such as collagenase, the activation of the immunesystem, for example by stimulation of T-helper cells, the activation ofosteoclast activity leading to the resorption of calcium, thestimulation of the release of proteoglycans from, for example,cartilage, the stimulation of cell proliferation and to angiogenesis.

Cytokines are also believed to be implicated in the production anddevelopment of disease states such as inflammatory and allergicdiseases, for example inflammation of the joints (especially rheumatoidarthritis, osteoarthritis and gout), inflammation of thegastrointestinal tract (especially inflammatory bowel disease,ulcerative colitis, Crohn's disease and gastritis), skin disease(especially psoriasis, eczema and dermatitis) and respiratory disease(especially asthma, bronchitis, allergic rhinitis and adult respiratorydistress syndrome), and in the production and development of variouscardiovascular and cerebrovascular disorders such as congestive heartdisease, myocardial infarction, the formation of atheroscleroticplaques, hypertension, platelet aggregation, angina, stroke, reperfusioninjury, vascular injury including restenosis and peripheral vasculardisease, and, for example, various disorders of bone metabolism such asosteoporosis (including senile and postmenopausal osteoporosis), Paget'sdisease, bone metastases, hypercalcaemia, hyperparathyroidism,osteosclerosis, osteoporosis and periodontitis, and the abnormal changesin bone metabolism which may accompany rheumatoid arthritis andosteoarthritis. Excessive cytokine production has also been implicatedin mediating certain complications of bacterial, fungal and/or viralinfections such as endotoxic shock, septic shock and toxic shocksyndrome and in mediating certain complications of CNS surgery or injurysuch as neurotrauma and ischaemic stroke. Excessive cytokine productionhas also been implicated in mediating or exacerbating the development ofdiseases involving cartilage or muscle resorption, pulmonary fibrosis,cirrhosis, renal fibrosis, the cachexia found in certain chronicdiseases such as malignant disease and acquired immune deficiencysyndrome (AIDS), tumour invasiveness and tumour metastasis and multiplesclerosis.

Evidence of the central role played by TNFα in the cell signallingcascade which gives rise to rheumatoid arthritis is provided by theefficacy in clinical studies of antibodies of TNFα (The Lancet, 1994,344, 1125 and British Journal of Rheumatology, 1995, 34, 334).

Thus cytokines such as TNFα and IL-1 are believed to be importantmediators of a considerable range of diseases and medical conditions.Accordingly it is expected that inhibition of the production of and/oreffects of these cytokines will be of benefit in the prophylaxis,control or treatment of such diseases and medical conditions.

Without wishing to imply that the compounds disclosed in the presentinvention possess pharmacological activity only by virtue of an effecton a single biological process, it is believed that the compoundsinhibit the effects of cytokines by virtue of inhibition of the enzymep38 kinase. p38 kinase, otherwise known as cytokine suppressive bindingprotein (hereinafter CSBP) and reactivating kinase (hereinafter RK), isa member of the mitogen-activated protein (hereinafter MAP) kinasefamily of enzymes which is known to be activated by physiological stresssuch as that induced by ionising radiation, cytotoxic agents, andtoxins, for example endotoxins such as bacterial lipopolysaccharide, andby a variety of agents such as the cytokines, for example TNFα and IL-1.It is known that p38 kinase phosphorylates certain intracellularproteins which are involved in the cascade of enzymatic steps whichleads to the biosynthesis and excretion of cytokines such as TNFα andIL-1. Known inhibitors of p38 kinase have been reviewed by G J Hanson inExpert Opinions on Therapeutic Patents, 1997, 7, 729-733. p38 kinase isknown to exist in isoforms identified as p38α and p38β.

European Patent Application No. 0 566 226, discloses certain quinazolinecompounds as tyrosine kinase-inhibiting anticancer agents including thecompounds:

4-(3-acetamidoanilino)-6,7-dimethoxyquinazoline and

4-(3-benzamidoanilino)-6,7-dimethoxyquinazoline.

The compounds disclosed in the present invention are inhibitors of theproduction of cytokines such as TNF, in particular of TNFα, and variousinterleukins, in particular IL-1.

According to one aspect of the present invention there is provided acompound of the Formula (I):

wherein:

G is N or CH;

R¹ is hydroxy, halo, trifluoromethyl, cyano, mercapto, nitro, amino,carboxy, carbamoyl, formyl, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₁₋₆alkoxy, —O—(C₁₋₃alkyl)—O—, C₁₋₆alkylS(O)_(n)— (whereinn is 0-2), N—C₁₋₆alkylamino, N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkoxycarbonyl,N—C₁₋₆alkylcarbamoyl, N,N—(C₁₋₆alkyl)₂carbamoyl, C₂₋₆alkanoyl,C₁₋₆alkanoyloxy, C₁₋₆alkanoylamino, N—C₁₋₆alkylsulphamoyl,N,N—(C₁₋₆alkyl)₂sulphamoyl, C₁₋₆alkylsulphonylamino,C₁₋₆alkylsulphonyl-N—(C₁₋₆alkyl)amino,

or R¹ is of the Formula (IA):

A—(CH₂)_(p)—B—  (IA)

wherein A is halo, hydroxy, C₁₋₆alkoxy, C₁₋₆alkylS(O)_(n)— (wherein n is0-2), cyano, amino, N—C₁₋₆alkylamino, N,N—(C₁₋₆alkyl)₂amino, carboxy,C₁₋₆alkoxycarbonyl, carbamoyl, N—C₁₋₆alkylcarbamoyl orN,N—(C₁₋₆alkyl)₂carbamoyl, p is 1-6, and B is a bond, oxy, imino,N—(C₁₋₆alkyl)imino or —C(O)NH—, with the proviso that p is 2 or moreunless B is a bond or —C(O)NH—,

or R¹ is of the Formula (IB):

D—E—  (IB)

wherein D is aryl, heteroaryl or heterocyclyl and E is a bond,C₁₋₆alkylene, C₁₋₆alkyleneoxy, oxy, imino, N—(C₁₋₆alkyl)imino,C₁₋₆alkyleneimino, N—(C₁₋₆alkyl)-C₁₋₆alkyleneimino,C₁₋₆alkyleneoxy-C₁₋₆alkylene, C₁₋₆alkyleneimino-C₁₋₆alkylene,N—(C₁₋₆alkyl)-C₁₋₆alkyleneimino-C₁₋₆alkylene, —C(O)NH—, —SO₂NH—, —NHSO₂—or C₂₋₆alkanoylimino, and any aryl, heteroaryl or heterocyclyl group ina R¹ group may be optionally substituted with one or more groupsselected from hydroxy, halo, C₁₋₆alkyl, C₁₋₆alkoxy, carboxy,C₁₋₆alkoxycarbonyl, carbamoyl, N—C₁₋₆alkylcarbamoyl,N,N—(C₁₋₆alkyl)₂carbamoyl, C₂₋₆alkanoyl, amino, N—C₁₋₆alkylamino andN,N—(C₁₋₆alkyl)₂amino, and any heterocyclyl group in a R¹ group may beoptionally substituted with one or two oxo or thioxo substituents,

and any of the R¹ groups defined hereinbefore which comprises a CH₂group which is attached to 2 carbon atoms or a CH₃ group which isattached to a carbon atom may optionally bear on each said CH₂ or CH₃group a substituent selected from hydroxy, amino, C₁₋₆alkoxy,

N—C₁₋₆alkylamino, N,N—(C₁₋₆alkyl)₂amino and heterocyclyl;

R² is hydrogen, halo, C₁₋₆alkyl, C₂₋₆alkenyl or C₂₋₆alkynyl;

R³ is hydrogen, halo, C₁₋₆alkyl, C₂₋₆alkenyl or C₂₋₆alkynyl;

R⁴ is hydrogen, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy, amino, N—C₁₋₆alkylamino,N,N—(C₁₋₆alkyl)₂amino, hydroxyC₂₋₆alkoxy, C₁₋₆alkoxyC₂₋₆alkoxy,aminoC₂₋₆alkoxy, N—C₁₋₆alkylaminoC₂₋₆alkoxy,N,N—(C₁₋₆alkyl)₂aminoC₂₋₆alkoxy or C₃₋₇cycloalkyl,

or R⁴ is of the Formula (IC):

—K—J  (IC)

wherein J is aryl, heteroaryl or heterocyclyl and K is a bond, oxy,imino, N—(C₁₋₆alkyl)imino, oxyC₁₋₆alkylene, iminoC₁₋₆alkylene,N—(C₁₋₆alkyl)iminoC₁₋₆alkylene, —NHC(O)—, —SO₂NH—, —NHSO₂— or—NHC(O)—C₁₋₆alkylene-,

and any aryl, heteroaryl or heterocyclyl group in a R⁴ group may beoptionally substituted by one or more groups selected from hydroxy,halo, trifluoromethyl, cyano, mercapto, nitro, amino, carboxy,carbamoyl, formyl, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆alkoxy, —O—(C₁₋₃alkyl)-O—, C₁₋₆alkylS(O)_(n)— (wherein n is 0-2),N—C₁₋₆alkylamino, N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkoxycarbonyl,N—C₁₋₆alkylcarbamoyl, N,N—(C₁₋₆alkyl)₂carbamoyl, C₂₋₆alkanoyl,C₁₋₆alkanoyloxy, C₁₋₆alkanoylamino, N—C₁₋₆alkylsulphamoyl,N,N—(C₁₋₆alkyl)₂sulphamoyl, C₁₋₆alkylsulphonylamino andC₁₋₆alkylsulphonyl-N—(C₁₋₆alkyl)amino,

or any aryl, heteroaryl or heterocyclyl group in a R⁴ group may beoptionally substituted with one or more groups of the Formula (IA′):

—B¹—(CH₂)_(p)—A¹  (IA′)

wherein A¹ is halo, hydroxy, C₁₋₆alkoxy, cyano, amino, N—C₁₋₆alkylamino,N,N—(C₁₋₆alkyl)₂amino, carboxy, C₁₋₆alkoxycarbonyl, carbamoyl,N—C₁₋₆alkylcarbamoyl or N,N—(C₁₋₆alkyl)₂carbamoyl, p is 1-6, and B¹ is abond, oxy, imino, N—(C₁₋₆alkyl)imino or —NHC(O)—, with the proviso thatp is 2 or more unless B¹ is a bond or —NHC(O)—;

or any aryl, heteroaryl or heterocyclyl group in a R⁴ group may beoptionally substituted with one or more groups of the Formula (IB′):

—E¹—D¹  (IB′)

wherein D¹ is aryl, heteroaryl or heterocyclyl and E¹ is a bond,C₁₋₆alkylene, oxyC₁₋₆alkylene, oxy, imino, N—(C₁₋₆alkyl)imino,iminoC₁₋₆alkylene, N—(C₁₋₆alkyl)iminoC₁₋₆alkylene,C₁₋₆alkylene-oxyC₁₋₆alkylene, C₁₋₆alkylene-iminoC₁₋₆alkylene,C₁₋₆alkylene-N—(C₁₋₆alkyl)iminoC₁₋₆alkylene, —NHC(O)—, —NHSO₂—, —SO₂NH—or —NHC(O)—C₁₋₆alkylene-, and any aryl, heteroaryl or heterocyclyl groupin a substituent on R⁴ may be optionally substituted with one or moregroups selected from hydroxy, halo, C₁₋₆alkyl, C₁₋₆alkoxy, carboxy,C₁₋₆alkoxycarbonyl, carbamoyl, N—C₁₋₆alkylcarbamoyl,N,N—(C₁₋₆alkyl)₂carbamoyl, C₂₋₆alkanoyl, amino, N—C₁₋₆alkylamino andN,N—(C₁₋₆alkyl)₂amino,

and any C₃₋₇cycloalkyl or heterocyclyl group in a R⁴ group may beoptionally substituted with one or two oxo or thioxo substituents,

and any of the R⁴ groups defined hereinbefore which comprises a CH₂group which is attached to 2 carbon atoms or a CH₃ group which isattached to a carbon atom may optionally bear on each said CH₂ or CH₃group a substituent selected from hydroxy, amino, C₁₋₆alkoxy,N—C₁₋₆alkylamino, N,N—(C₁₋₆alkyl)₂amino and heterocyclyl;

R⁵ is hydrogen, halo, trifluoromethyl, cyano, nitro, amino, hydroxy,C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy, N—C₁₋₆alkylamino orN,N—(C₁₋₆alkyl)₂amino;

m is 1, 2 or 3; and

q is 0, 1, 2, 3 or 4;

or a pharmaceutically acceptable salt or an in vivo cleavable esterthereof; with the proviso that:

4-(3-acetamidoanilino)-6,7-dimethoxyquinazoline; and

4-(3-benzamidoanilino)-6,7-dimethoxyquinazoline are excluded.

According to a further aspect of the present invention there is provideda compound of the Formula (I) wherein:

G is N or CH;

R¹ is hydroxy, halo, trifluoromethyl, cyano, mercapto, nitro, amino,carboxy, carbamoyl, formyl, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₁₋₆alkoxy, —O—(C₁₋₃alkyl)-O—, C₁₋₆alkylS(O)_(n)— (whereinn is 0-2), N—C₁₋₆alkylamino, N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkoxycarbonyl,N—C₁₋₆alkylcarbamoyl, N,N—(C₁₋₆alkyl)₂carbamoyl, C₂₋₆alkanoyl,C₁₋₆alkanoyloxy, C₁₋₆alkanoylamino, N—C₁₋₆alkylsulphamoyl,N,N—(C₁₋₆alkyl)₂sulphamoyl, C₁₋₆alkylsulphonylamino,C₁₋₆alkylsulphonyl-N—(C₁₋₆alkyl)amino, or R¹ is of the formula:

A—(CH₂)_(p)—B—  (IA)

wherein A is halo, hydroxy, C₁₋₆alkoxy, cyano, amino, N—C₁₋₆alkylamino,N,N—(C₁₋₆alkyl)₂amino, carboxy, C₁₋₆alkoxycarbonyl, carbamoyl,N—C₁₋₆alkylcarbamoyl or N,N—(C₁₋₆alkyl)₂carbamoyl, p is 1-6, and B is abond, oxy, imino, N—(C₁₋₆alkyl)imino or —C(O)NH—, with the proviso thatp is 2 or more unless B is a bond or —C(O)NH—, or R¹ is of the formula:

D—E—  (IB)

wherein D is aryl, heteroaryl or heterocyclyl and E is a bond,C₁₋₆alkylene, C₁₋₆alkyleneoxy, oxy, imino, N—(C₁₋₆alkyl)imino,C₁₋₆alkyleneimino, N—(C₁₋₆alkyl)-C₁₋₆alkyleneimino, —C(O)NH—, —SO₂NH—,—NHSO₂— or C₂₋₆alkanoylimino, and any aryl, heteroaryl or heterocyclylgroup may be optionally substituted with one or more groups selectedfrom hydroxy, halo, C₁₋₆alkyl, C₁₋₆alkoxy, carboxy, C₁₋₆alkoxycarbonyl,carbamoyl, N—C₁₋₆alkylcarbamoyl, N—(C₁₋₆alkyl)₂carbamoyl, C₂₋₆alkanoyl,amino, N—C₁₋₆alkylamino and N,N—(C₁₋₆alkyl)₂amino;

R² is hydrogen, halo, C₁₋₆alkyl, C₂₋₆alkenyl or C₂₋₆alkynyl;

R³ is hydrogen, halo, C₁₋₆alkyl, C₂₋₆alkenyl or C₂₋₆alkynyl;

R⁴ is hydrogen, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy, amino, N—C₁₋₆alkylamino,N,N—(C₁₋₆alkyl)₂amino, hydroxyC₂₋₆alkoxy, C₁₋₆alkoxyC₂₋₆alkoxy,aminoC₂₋₆alkoxy, N—C₁₋₆alkylaminoC₂₋₆alkoxy,N,N—(C₁₋₆alkyl)₂aminoC₂₋₆alkoxy or C₃₋₇cycloalkyl, or R⁴ is of theformula:

—K—J  (IC)

wherein J is aryl, heteroaryl or heterocyclyl and K is a bond, oxy,imino, N—(C₁₋₆alkyl)imino, oxyC₁₋₆alkylene, iminoC₁₋₆alkylene,N—(C₁₋₆alkyl)iminoC₁₋₆alkylene, —NHC(O)—, —SO₂NH—, —NHSO₂— or—NHC(O)—C₁₋₆alkylene-, and any aryl, heteroaryl or heterocyclyl groupmay be optionally substituted by one or more groups selected fromhydroxy, halo, trifluoromethyl, cyano, mercapto, nitro, amino, carboxy,carbamoyl, formyl, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆alkoxy, —O—(C₁₋₃alkyl)-O—, C₁₋₆alkylS(O)_(n)— (wherein n is 0-2),N—C₁₋₆alkylamino, N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkoxycarbonyl,N—C₁₋₆alkylcarbamoyl, N,N—(C₁₋₆alkyl)₂carbamoyl, C₂₋₆alkanoyl,C₁₋₆alkanoyloxy, C₁₋₆alkanoylamino, N—C₁₋₆alkylsulphamoyl,N,N—(C₁₋₆alkyl)₂sulphamoyl, C₁₋₆alkylsulphonylamino andC₁₋₆alkylsulphonyl-N—(C₁₋₆alkyl)amino, or any aryl, heteroaryl orheterocyclyl may be optionally substituted with one or more groups ofthe formula (IA′):

—B¹—(CH₂)_(p)—A¹  (IA′)

wherein A¹ is halo, hydroxy, C₁₋₆alkoxy, cyano, amino, N—C₁₋₆alkylamino,N,N—(C₁₋₆alkyl)₂amino, carboxy, C₁₋₆alkoxycarbonyl, carbamoyl,N—C₁₋₆alkylcarbamoyl or N,N—(C₁₋₆alkyl)₂carbamoyl, p is 1-6, and B¹ is abond, oxy, imino, N—(C₁₋₆alkyl)imino or —NHC(O)—, with the proviso thatp is 2 or more unless B¹ is a bond or —NHC(O)—; and/or (IB′):

—E¹—D¹  (IB)

wherein D¹ is aryl, heteroaryl or heterocyclyl and E¹ is a bond,C₁₋₆alkylene, oxyC₁₋₆alkylene, oxy, imino, N—(C₁₋₆alkyl)imino,iminoC₁₋₆alkylene, N—(C₁₋₆alkyl)iminoC₁₋₆alkylene, —NHC(O)—, —NHSO₂—,—SO₂NH— or —NHC(O)—C₁₋₆alkylene-, and any aryl, heteroaryl orheterocyclyl group may be optionally substituted with one or more groupsselected from hydroxy, halo, C₁₋₆alkyl, C₁₋₆alkoxy, carboxy,C₁₋₆alkoxycarbonyl, carbamoyl, N—C₁₋₆alkylcarbamoyl,N,N—(C₁₋₆alkyl)₂carbamoyl, C₂₋₆alkanoyl, amino, N—C₁₋₆alkylamino andN,N—(C₁₋₆alkyl)₂amino;

R⁵ is hydrogen, halo, trifluoromethyl, cyano, nitro, amino, hydroxy,C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy, N—C₁₋₆alkylamino orN,N—(C₁₋₆alkyl)₂amino;

m is 1, 2 or 3;

q is 0, 1, 2, 3 or 4;

or a pharmaceutically acceptable salt or an in vivo cleavable esterthereof, with the proviso that:

4-(3-acetamidoanilino)-6,7-dimethoxyquinazoline; and

4-(3-benzamidoanilino)-6,7-dimethoxyquinazoline are excluded.

In this specification the term “alkyl” includes both straight andbranched chain alkyl groups but references to individual alkyl groupssuch as “propyl” are specific for the straight chain version only. Forexample, “C₁₋₆alkyl” includes propyl, isopropyl and tert-butyl. However,references to individual alkyl groups such as ‘propyl’ are specific forthe straight chained version only and references to individual branchedchain alkyl groups such as ‘isopropyl’ are specific for the branchedchain version only. A similar convention applies to other radicals, forexample “aminoC₂₋₆alkoxy” includes 2-aminoethoxy, 2-aminopropoxy and3-amino-2-methylpropoxy. The term “halo” refers to fluoro, chloro, bromoand iodo.

The term “aryl” refers to phenyl or naphthyl.

The term “heteroaryl” refers to, unless otherwise further specified, amonocyclic-, bicyclic- or tricyclic-5-14 membered ring that containssome degree of unsaturation, with up to five ring heteroatoms selectedfrom nitrogen, oxygen and sulphur wherein a —CH₂— group can optionallybe replaced by a —C(O)—, a ring nitrogen atom may optionally bear aC₁₋₆alkyl group or a ring nitrogen atom may be optionally oxidised toform the N-oxide. Examples of “heteroaryl” include thienyl, furyl,pyranyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl,isoxazolyl, pyridyl, pyridyl-N-oxide. oxopyridyl, oxoquinolyl,pyrimidinyl, pyrazinyl, oxopyrazinyl, pyridazinyl, indolyl,benzofuranyl, benzimidazolyl, benzothiazoly, quinolyl,N-methyloxoquinolyl, isoquinolinyl, quinazolinyl, xanthenyl,quinoxalinyl, indazolyl, benzofuranyl and cinnolinolyl.

The term “heterocyclyl” refers to, unless otherwise further specified, amono- or bicyclic-5-14 membered ring, that is totally saturated, with upto five ring heteroatoms selected from nitrogen, oxygen and sulphurwherein a —CH₂— group can optionally be replaced by a —C(O)— or a ringnitrogen atom may optionally bear a C₁₋₆alkyl group. Examples of suchheterocyclyls include morpholinyl, N-methylmorpholinyl, pyrrolidinyl,imidazolidinyl, pyrazolidinyl, piperidinyl, homopiperidinyl,N-methylpiperidinyl, piperazinyl, homopiperazinyl and quinuclidinyl.

Where optional substituents are chosen from “one or more” groups it isto be understood that this definition includes all substituents beingchosen from one of the specified groups or the substituents being chosenfrom two or more of the specified groups. Conveniently there may be 1, 2or 3 such optional substituents. For example, where optionalsubstituents are chosen from one or more groups selected from halo,C₁₋₆alkoxy and C₁₋₆alkyl, examples of possible combinations ofsubstituents include 1) a bromo group, 2) two chloro groups, 3) amethoxy, ethoxy and propoxy substituent, 4) a fluoro and a methoxygroup, 5) a methoxy, a methyl and an ethyl group, and 6) a chloro, amethoxy and an ethyl group.

It is to be understood that the bicyclic ring within the compound ofFormula (I) is shown with a hydrogen atom attached to the carbon betweenthe N atom and G group in order to indicate that this position isunsubstituted. Thereby it is to be understood that that hydrogen atommay not be replaced by a R¹ substituent. It should also be understoodhowever that when G is a CH group such that the bicyclic ring is aquinoline ring the 3-position of the quinoline ring may bear any one ofthe R¹ substituents.

The following table gives examples of radicals that fall within thedefinition of the generic terms used in this specification:

Generic Term Example of Radical C₁₋₄alkyl methyl, ethyl, isopropylC₁₋₆alkoxycarbonyl methoxycarbonyl, ethoxycarbonyl, n- andtert-butoxycarbonyl C₁₋₆alkoxy methoxy, ethoxy, propoxy C₁₋₄alkoxymethoxy, ethoxy, propoxy C₂₋₄alkoxy ethoxy, propoxy, t-butoxyC₁₋₆alkanoylamino formamido, acetamido, propionylamino C₁₋₆alkylS(O)_(n)where n is 0-2 methylthio, ethylthio, methylsulphinyl, ethylsulphinyl,mesyl, ethylsulphonyl C₂₋₆alkanoyl propionyl, acetyl N—C₁₋₆alkylaminoN-methylamino, N-ethylamino N,N-(C₁₋₆alkyl)₂amino N,N-dimethylamino,N,N-diethylamino, N-ethyl-N-methylamino C₁₋₆alkoxyC₂₋₆alkoxy2-methoxyethoxy, 4-propoxybutoxy N-(C₁₋₆alkyl)aminoC₂₋₆alkoxy3-(N-methylamino)propoxy, 4-(N-ethylamino)butoxyN,N-(C₁₋₆alkyl)₂aminoC₂₋₆alkoxy 2-(N,N-dimethylamino)ethoxy,3-(N-methyl-N-ethylamino)propoxy C₃₋₇cycloalkyl cyclopropyl, cyclohexylC₂₋₆alkenyl vinyl, allyl, 1-propenyl C₂₋₆alkynyl ethynyl, 1-propynyl,2-propynyl hydroxyC₂₋₆alkoxy 2-hydroxyethoxy, 2-hydroxypropoxyC₁₋₆alkylsulphonylamino methanesulphonamido, ethanesulphonamidoC₁₋₆alkylsulphonyl-N-(C₁₋₆alkyl)amino N-ethylmethanesulphonamido,N-butylethanesulphonamido N-(C₁₋₆alkyl)sulphamoyl N-methylsulphamoyl,N-ethylsulphamoyl N,N-(C₁₋₆alkyl)₂sulphamoyl N,N-dimethylsulphamoyl,N-methyl-N-ethylsulphamoyl N-(C₁₋₆alkyl)carbamoyl N-methylcarbamoyl,N-ethylcarbamoyl N,N-(C₁₋₆alkyl)₂carbamoyl N,N-dimethylcarbamoyl,N-methyl-N-ethylcarbamoyl C₁₋₆alkanoyloxy propionyloxy, acetyloxy,formyloxy —O—C₁₋₃alkyl-O— methylenedioxy, ethylenedioxy (i.e. abidentate substituent, attached to the ring in two adjacent positions)

In the linking groups B, E, B¹, E¹ and K that fall within the definitionof R¹ and R⁴, the following table gives examples of radicals that fallwithin these general terms:

Generic Term Example of Radical C₁₋₆alkylene —CH₂CH₂—, —CH₂CH(CH₃)CH₂—C₁₋₆alkyleneoxy —CH₂CH₂O—, —CH₂CH(CH₃)CH₂O— N—(C₁₋₆alkyl)imino —N(Me)—,—N(^(i)Pr)— C₁₋₆alkyleneimino —CH₂CH₂NH—, —CH₂CH(CH₃)CH₂NH—N—(C₁₋₆alkyl)-C₁₋₆alkyleneimino —CH₂CH₂N(Me)—, —CH₂CH(CH₃)CH₂N(^(i)Pr)—C₂₋₆alkanoylimino —CH₂CH₂C(O)NH—, —CH₂CH(CH₃)CH₂C(O)NH— oxyC₁₋₆alkylene—OCH₂CH₂—, —OCH₂CH(CH₃)CH₂— iminoC₁₋₆alkylene —NHCH₂CH₂—,—NHCH₂CH(CH₃)CH₂— N—(C₁₋₆alkyl)iminoC₁₋₆alkylene —N(Me)CH₂CH₂—,—N(^(i)Pr)CH₂CH(CH₃)CH₂— —NHC(O)C₁₋₆alkylene- —NHC(O)CH₂CH₂—,—NHC(O)CH₂CH(CH₃)CH₂—

For the avoidance of doubt, it is to be understood that when, forexample, R¹ is a group of the Formula (IB):

D—E—  (IB)

and the linking group E is, for example, a C₁₋₆alkyleneoxy group such as—CH₂CH₂O—, it is a CH₂ group which is attached to D and the O atom whichis attached to the bicyclic ring within Formula (I). Similarly when, forexample, R⁴ is a group of the Formula (IB′):

—E¹—D¹  (IB′)

and the linking group E¹ is, for example, an iminoC₁₋₆alkylene groupsuch as —NHCH₂CH₂—, it is a CH₂ group which is attached to D¹ and the NHgroup which is attached to the bicyclic ring within Formula (I). Ananalogous convention applies to other bidentate linking groups.

It is to be understood that, insofar as certain of the compounds of theFormula (I) defined above may exist in optically active or racemic formsby virtue of one or more asymmetric carbon atoms, the invention includesin its definition any such optically active or racemic form whichpossesses the property of inhibiting cytokines, in particular TNF. Thesynthesis of optically active forms may be carried out by standardtechniques of organic chemistry well known in the art, for example bysynthesis from optically active starting materials or by resolution of aracemic form. Similarly, inhibitory properties against TNF may beevaluated using the standard laboratory techniques referred tohereinafter.

Preferable values of R¹, R², R³, R⁴, R⁵, G, q and m are as follows.

Preferably R¹ is hydroxy, halo, C₁₋₆alkoxy,N,N—(C₁₋₆alkyl)₂aminoC₁₋₆alkyl, N,N—(C₁₋₆alkyl)₂carbamoylC₁₋₆alkoxy,N,N—(C₁₋₆alkyl)₂aminoC₁₋₆alkoxy, C₁₋₆alkylS(O)₂—C₁₋₆alkoxy,N,N—(C₁₋₆alkyl)₂amino-N—(C₁₋₆alkyl)C₁₋₆alkylamino,N,N—(C₁₋₆alkyl)₂aminoC₁₋₆alkylaminoC₁₋₆alkyl, heterocyclylC₁₋₆alkyl,heterocyclylC₁₋₆alkoxy, heterocyclyloxy,heterocyclylC₁₋₆alkylaminoC₁₋₆alkyl or heteroarylC₁₋₆alkoxy.

More preferably R¹ is hydroxy, halo, C₁₋₆alkoxy,N,N—(C₁₋₆alkyl)₂aminoC₁₋₆alkyl, N,N—(C₁₋₆alkyl)₂carbamoylC₁₋₆alkoxy,N,N—(C₁₋₆alkyl)₂aminoC₁₋₆alkoxy, C₁₋₆alkylS(O)₂—C₁₋₆alkoxy,N,N—(C₁₋₆alkyl)₂amino-N—(C₁₋₆alkyl)C₁₋₆alkylamino,N,N—(C₁₋₆alkyl)₂aminoC₁₋₆alkylaminoC₁₋₆alkyl, piperazin-1-ylC₁₋₆alkyl,4-C₁₋₆alkylpiperazin-1-ylC₁₋₆alkyl, homopiperazinyl-1-ylC₁₋₆alkyl,4-C₁₋₆alkylhomopiperazinyl-1-ylC₁₋₆alkyl, pyrrolidinylC₁₋₆alkoxy,piperidinylC₁₋₆alkoxy, N—(C₁₋₆alkyl)pyrrolidinylC₁₋₆alkoxy,N—(C₁₋₆alkyl)piperidinylC₁₋₆alkoxy, morpholinylC₁₋₆alkoxy,piperazinylC₁₋₆alkoxy, N—(C₁₋₆alkyl)piperazinylC₁₋₆alkoxy,homopiperazinylC₁₋₆alkoxy, N—(C₁₋₆alkyl)homopiperazinylC₁₋₆alkoxy,pyrrolidinyloxy, piperidinyloxy, morpholinylC₁₋₆alkylaminoC₁₋₆alkyl orpyridylC₁₋₆alkoxy.

More particularly R¹ is methoxy, 2-dimethylaminoethoxy,2-diethylaminoethoxy, 2-diisopropylaminoethoxy, 3-dimethylaminopropoxy,3-diethylaminopropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy,2-piperidinoethoxy, N-methylpiperidin-2-ylmethoxy,N-methylpiperidin-3-ylmethoxy, 2-pyrrolidin-1-ylethoxy,2-(N-methylpyrrolidin-2-yl)ethoxy, N-methyl-5-oxopyrrolidin-2-ylmethoxy,3-pyrrolidin-1-ylpropoxy, 2-(2-oxoimidazolidin-1-yl)ethoxy,2-(4-methylpiperazin-1-yl)ethoxy or 3-pyrid-3-ylpropoxy.

Further more particularly R¹ is methoxy, 2-diisopropylaminoethoxy,3-diethylaminopropoxy, 3-morpholinopropoxy or 3-pyrrolidin-1-ylpropoxy.

More preferably R¹ is C₁₋₆alkoxy, heterocyclylC₁₋₆alkoxy orheteroarylC₁₋₆alkoxy.

More preferably R¹ is C₁₋₆alkoxy, morpholinylC₁₋₆alkoxy,pyrrolidinylC₁₋₆alkoxy, pyridylC₁₋₆alkoxy, piperidin-1-ylC₁₋₆alkoxy,piperazin-1-ylC₁₋₆alkoxy or 4-C₁₋₆alkylpiperazinyl-1-ylC₁₋₆alkoxy.

Particularly R¹ is C₁₋₆alkoxy, morpholinylC₂₋₄alkoxy,pyrrolidinylC₂₋₄alkoxy or pyridylC₂₋₄alkoxy.

More particularly R¹ is methoxy, 2-morpholinoethoxy,3-morpholinopropoxy, 2-pyrrolidin-1-ylethoxy or 3-pyrid-3-ylpropoxy.

Preferably R² is hydrogen, C₁₋₆alkyl or halo.

More preferably R² is hydrogen, C₁₋₄alkyl or halo.

Particularly R² is hydrogen, methyl, fluoro or chloro.

More particularly R² is C₁₋₄alkyl or halo when R³ is hydrogen.

Preferably R³ is hydrogen, C₁₋₆alkyl or halo.

More preferably R³ is hydrogen, C₁₋₄alkyl or halo.

Particularly R³ is hydrogen, methyl, fluoro or chloro.

More particularly R³ is C₁₋₄alkyl or halo when R² is hydrogen.

Preferably R⁴ is hydrogen or C₁₋₆alkoxy or R⁴ is aryl or heteroaryloptionally substituted by one or more groups selected from halo, cyano,C₁₋₆alkyl, C₁₋₆alkoxy, N,N—(C₁₋₆alkyl)₂amino or heterocyclyl.

More preferably R⁴ is hydrogen or C₁₋₆alkoxy or R⁴ is aryl or heteroaryloptionally substituted by one or more groups selected from halo, cyano,C₁₋₆alkyl, C₁₋₆alkoxy, N,N—(C₁₋₆alkyl)₂amino, pyrrolidin-1-yl,piperidinyl, morpholino, piperazinyl, 4-C₁₋₆alkylpiperazin-1-yl,homopiperazinyl-1-yl or 4-C₁₋₆alkylhomopiperazinyl-1-yl.

More preferably R⁴ is hydrogen or C₁₋₆alkoxy or R⁴ is aryl or heteroaryloptionally substituted by one or more groups selected from halo, cyano,C₁₋₆alkyl, C₁₋₆alkoxy, N,N—(C₁₋₆alkyl)₂amino, piperazinyl, morpholino orpiperazinyl.

More preferably R⁴ is hydrogen or C₁₋₆alkoxy or R⁴ is phenyl, thienyl,furyl, oxazolyl, isoxazolyl, pyrimidyl or pyridyl optionally substitutedby one or two halo, cyano, C₁₋₄alkyl, C₁₋₄alkoxy, N,N—(C₁₋₄alkyl)₂amino,piperidinyl, morpholino or piperazinyl.

Particularly R⁴ is hydrogen or methoxy or R⁴ is phenyl, furyl,isoxazolyl or pyridyl optionally substituted by one or more groupsselected from fluoro, chloro, cyano, methyl, methoxy, N,N-dimethylaminoor morpholino.

More particularly R⁴ is hydrogen, methoxy, phenyl, 2-methylphenyl,3-(N,N-dimethylamino)phenyl, 3-fluorophenyl, 3-methoxyphenyl,4-cyanophenyl, 3,4-dimethoxyphenyl, 3-morpholinophenyl, 2-furyl,2-chloropyrid-5-yl, 2-morpholinopyrid-4-yl or isoxazol-5-yl.

Further more particularly R⁴ is pyridyl optionally substituted by aN,N-dimethylamino, N,N-diethylamino, pyrrolidin-1-yl, piperidino ormorpholino group.

Even more particularly R⁴ is 2-morpholinopyrid-4-yl.

Preferably R⁵ is hydrogen.

Preferably G is N.

Preferably m is 2 or 3.

Particularly m is 1, 2 or 3.

Preferably q is 0 or 1.

When, as defined hereinbefore, any of the R¹ or R⁴ groups definedhereinbefore which comprises a CH₂ group which is attached to 2 carbonatoms or a CH₃ group which is attached to a carbon atom may optionallybear on each said CH₂ or CH₃ group a substituent selected from hydroxy,amino, C₁₋₆alkoxy, N—C₁₋₆alkylamino, N,N—(C₁₋₆alkyl)₂amino andheterocyclyl, suitable substituents so formed include, for example,substituted heterocyclylC₁₋₆alkoxy groups such as2-hydroxy-3-piperidinopropoxy and 2-hydroxy-3-morpholinopropoxy,substituted aminoC₁₋₆alkoxy groups such as 3-amino-2-hydroxypropoxy,substituted N—C₁₋₆alkylaminoC₁₋₆alkoxy groups such as2-hydroxy-3-methylaminopropoxy, substitutedN,N—(C₁₋₆alkyl)₂aminoC₁₋₆alkoxy groups such as3-dimethylamino-2-hydroxypropoxy,3-[N-(3-dimethylaminopropyl)-N-methylamino]propoxy and3-[N-(3-dimethylaminopropyl)-N-methylamino]-2-hydroxypropoxy,substituted heterocyclylC₁₋₆alkylamino groups such as2-hydroxy-3-piperidinopropylamino and 2-hydroxy-3-morpholinopropylamino,substituted aminoC₁₋₆alkylamino groups such as3-amino-2-hydroxypropylamino, substituted N—C₁₋₆alkylaminoC₁₋₆alkylaminogroups such as 2-hydroxy-3-methylaminopropylamino, substitutedN,N—(C₁₋₆alkyl)₂aminoC₁₋₆alkylamino groups such as3-dimethylamino-2-hydroxypropylamino,3-[N-(3-dimethylaminopropyl)-N-methylamino]propylamino and3-[N-(3-dimethylaminopropyl)-N-methylamino]-2-hydroxypropylamino,substituted N—C₁₋₆alkylaminoC₁₋₆alkyl groups such as2-dimethylaminoethylaminomethyl, 3-dimethylaminopropylaminomethyl,3-dimethylamino-2,2-dimethylpropylaminomethyl,2-morpholinoethylaminomethyl, 2-piperazin-1-ylethylaminomethyl and3-morpholinopropylaminomethyl.

Preferred combinations of q and R⁴ are as follows.

When q is 0, preferably R⁴ is hydrogen or C₁₋₆alkoxy or R⁴ is aryl orheteroaryl optionally substituted by one or more groups selected fromhalo, cyano, C₁₋₆alkyl, C₁₋₆alkoxy, N,N—(C₁₋₆alkyl)₂amino, piperazinyl,morpholino or piperazinyl. When q is 1, preferably R⁴ is hydrogen orC₁₋₆alkoxy. When q is 2 preferably R⁴ is hydrogen.

When q is 0, more preferably R⁴ is hydrogen or C₁₋₆alkoxy or R⁴ isphenyl, thienyl, furyl, oxazolyl, isoxazolyl, pyrimidyl or pyridyloptionally substituted by one or two halo, cyano, C₁₋₄alkyl, C₁₋₄alkoxy,N,N—(C₁₋₄alkyl)₂amino, piperazinyl, morpholino or piperazinyl groups.When q is 1, more preferably R⁴ is hydrogen or C₁₋₄alkoxy.

When q is 0, particularly R⁴ is hydrogen or methoxy or R⁴ is phenyl,furyl, isoxazolyl or pyridyl optionally substituted by one or moregroups selected from fluoro, chloro, cyano, methyl, methoxy,N,N-dimethylamino or morpholino. When q is 1, particularly R⁴ ishydrogen or methoxy.

When q is 0, more particularly R⁴ is hydrogen, methoxy, phenyl,2-methylphenyl, 3-(N,N-dimethylamino)phenyl, 3-fluorophenyl,3-methoxyphenyl, 4-cyanophenyl, 3,4-dimethoxyphenyl, 3-morpholinophenyl,2-furyl, 2-chloropyrid-5-yl, 2-morpholino-pyridyl-4-yl or isoxazol-5-yl.

Preferred combinations of R¹ and m are as follows.

When m is 2, preferably R¹ is C₁₋₆alkoxy, heterocyclylC₁₋₆alkoxy orheteroarylC₁₋₆alkoxy. When m is 3, preferably R¹ is C₁₋₆alkoxy.

When m is 2, more preferably R¹ is C₁₋₄alkoxy, morpholinylC₂₋₄alkoxy,pyrrolidinylC₂₋₄alkoxy or pyridylC₂₋₄alkoxy. When m is 3, preferably R¹is C₁₋₄alkoxy.

When m is 2 particularly R¹ is methoxy, 2-morpholinoethoxy,3-morpholinopropoxy, 2-pyrrolidin-1-ylethoxy or 3-pyrid-3-ylpropoxy.When m is 3, particularly R¹ is methoxy.

When m is 2 more particularly (R¹)_(m) is 6,7-dimethoxy,6-methoxy-7-[2-morpholinoethoxy], 6-methoxy-7-[3-morpholinopropoxy],6-methoxy-7-(2-pyrrolidin-1-ylethoxy) or6-methoxy-7-(3-pyrid-3-ylpropoxy). When m is 3, more particularly(R¹)_(m) is 6,7,8-trimethoxy.

In one embodiment of the invention R⁴ is hydrogen, hydroxy, C₁₋₆alkyl,C₁₋₆alkoxy, amino, N—C₁₋₆alkylamino, N,N—(C₁₋₆alkyl)₂amino,hydroxyC₂₋₆alkoxy, C₁₋₆alkoxy-C₂₋₆alkoxy, aminoC₂₋₆alkoxy,N—C₁₋₆alkylaminoC₂₋₆alkoxy or N,N—(C₁₋₆alkyl)₂amino-C₂₋₆alkoxy.

In a further embodiment of the invention R⁴ is of the Formula:

—K—J  (IC)

wherein J is aryl, heteroaryl or heterocyclyl and K is a bond, oxy,imino, N—(C₁₋₆alkyl)imino, oxyC₁₋₆alkylene, iminoC₁₋₆alkylene,N—(C₁₋₆alkyl)iminoC₁₋₆alkylene, —NHC(O)—, —SO₂NH—, —NHSO₂— or—NHC(O)—C₁₋₆alkylene-, and any aryl, heteroaryl or heterocyclyl may beoptionally substituted by one or more groups selected from hydroxy,halo, trifluoromethyl, cyano, mercapto, nitro, amino, carboxy,carbamoyl, formyl, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆alkoxy, —O—(C₁₋₃alkyl)-O—, C₁₋₆alkylS(O)_(n)— (wherein n is 0-2),N—C₁₋₆alkyl amino, N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkoxycarbonyl,N—C₁₋₆alkylcarbamoyl, N,N—(C₁₋₆alkyl)₂carbamoyl, C₂₋₆alkanoyl,C₁₋₆alkanoyloxy, C₁₋₆alkanoylamino, N—C₁₋₆alkylsulphamoyl,N,N—(C₁₋₆alkyl)₂sulphamoyl, C₁₋₆alkylsulphonylamino andC₁₋₆alkylsulphonyl-N—(C₁₋₆alkyl)amino, or any aryl, heteroaryl orheterocyclyl may be optionally substituted with one or more groups ofthe Formula (IA′) or (IB′) wherein A¹, B¹, D¹ and E¹ are as defined forFormula (I).

In another embodiment of the invention G is CH.

Another aspect of the present invention provides a compound of theFormula (I) (as depicted above) wherein:

R¹ is hydroxy, halo, C₁₋₆alkoxy, N,N—(C₁₋₆alkyl)₂aminoC₁₋₆alkyl,N,N—(C₁₋₆alkyl)₂carbamoylC₁₋₆alkoxy, N,N—(C₁₋₆alkyl)₂aminoC₁₋₆alkoxy,C₁₋₆alkylS(O)₂—C₁₋₆alkoxy,N,N(C₁₋₆alkyl)₂amino-N—(C₁₋₆alkyl)C₁₋₆alkylamino,N,N—(C₁₋₆alkyl)₂aminoC₁₋₆alkylaminoC₁₋₆alkyl, heterocyclylC₁₋₆alkyl,heterocyclyl-C₁₋₆alkoxy, heterocyclyloxy,heterocyclylC₁₋₆alkylaminoC₁₋₆alkyl or heteroarylC₁₋₆alkoxy;

R² is hydrogen, C₁₋₆alkyl or halo;

R³ is hydrogen, C₁₋₆alkyl or halo;

R⁴ is hydrogen or C₁₋₆alkoxy or R⁴ is aryl or heteroaryl optionallysubstituted by one or more groups selected from halo, cyano, C₁₋₆alkyl,C₁₋₆alkoxy, N,N—(C₁₋₆alkyl)₂amino or heterocyclyl;

R⁵ is hydrogen;

G is N;

m is 1, 2 or 3; and

q is 0 or 1;

or a pharmaceutically acceptable salt, or an in vivo cleavable esterthereof.

A further aspect of the present invention provides a compound of theFormula (I) (as depicted above) wherein:

R¹ is hydroxy, halo, C₁₋₆alkoxy, N,N—(C₁₋₆alkyl)₂aminoC₁₋₆alkyl,N,N—(C₁₋₆alkyl)₂carbamoylC₁₋₆alkoxy, N,N—(C₁₋₆alkyl)₂aminoC₁₋₆alkoxy,C₁₋₆alkylS(O)₂—C₁₋₆alkoxy,N,N—(C₁₋₆alkyl)₂amino-N—(C₁₋₆alkyl)C₁₋₆alkylamino,N,N—(C₁₋₆alkyl)₂aminoC₁₋₆alkylaminoC₁₋₆alkyl, piperazin-1-ylC₁₋₆alkyl,4-C₁₋₆alkylpiperazin-1-ylC₁₋₆alkyl, homopiperazinyl-1-ylC₁₋₆alkyl,4-C₁₋₆alkylhomopiperazinyl-1-ylC₁₋₆alkyl, pyrrolidinylC₁₋₆alkoxy,piperidinylC₁₋₆alkoxy, N—(C₁₋₆alkyl)pyrrolidinylC₁₋₆alkoxy,N—(C₁₋₆alkyl)piperidinylC₁₋₆alkoxy,morpholinylC₁₋₆alkoxy,piperazinylC₁₋₆alkoxy, N—(C₁₋₆alkyl)piperazinylC₁₋₆alkoxy,homopiperazinylC₁₋₆alkoxy, N—(C₁₋₆alkyl)homopiperazinylC₁₋₆alkoxy,pyrrolidinyloxy, piperidinyloxy, morpholinylC₁₋₆alkylaminoC₁₋₆alkyl orpyridylC₁₋₆alkoxy;

R² is hydrogen, C₁₋₆alkyl or halo;

R³ is hydrogen, C₁₋₆alkyl or halo;

R⁴ is hydrogen or C₁₋₆alkoxy or R⁴ is aryl or heteroaryl optionallysubstituted by one or more groups selected from halo, cyano, C₁₋₆alkyl,C₁₋₆alkoxy, N,N—(C₁₋₆alkyl)₂amino, pyrrolidin-1-yl, piperidinyl,morpholino, piperazinyl, 4-C₁₋₆alkylpiperazin-1-yl, homopiperazinyl-1-ylor 4-C₁₋₆alkylhomopiperazinyl-1-yl;

R⁵ is hydrogen;

G is N;

m is 1, 2 or 3; and

q is 0 or 1;

or a pharmaceutically acceptable salt, or an in vivo cleavable esterthereof.

A further aspect of the present invention provides a compound of theFormula (I) (as depicted above) wherein:

R¹ is C₁₋₆alkoxy, heterocyclylC₁₋₆alkoxy or heteroarylC₁₋₆alkoxy;

R² is hydrogen, C₁₋₆alkyl or halo;

R³ is hydrogen, C₁₋₆alkyl or halo;

R⁴ is hydrogen or C₁₋₆alkoxy or R⁴ is aryl or heteroaryl optionallysubstituted by one or more groups selected from halo, cyano, C₁₋₆alkyl,C₁₋₆alkoxy or N,N—(C₁₋₆alkyl)₂amino;

R⁵ is hydrogen;

G is N;

m is 2 or 3; and

q is 0 or 1;

or a pharmaceutically acceptable salt, or an in vivo cleavable esterthereof.

A further aspect of the present invention provides a compound of theFormula (I) (as depicted above) wherein:

R¹ is C₁₋₆alkoxy, morpholinylC₁₋₆alkoxy, pyrrolidinylC₁₋₆alkoxy orpyridylC₁₋₆alkoxy;

R² is hydrogen, C₁₋₆alkyl or halo;

R³ is hydrogen, C₁₋₆alkyl or halo;

R⁴ is hydrogen or C₁₋₆alkoxy or R⁴ is aryl or heteroaryl optionallysubstituted by one or more groups selected from halo, cyano, C₁₋₆alkyl,C₁₋₆alkoxy, N,N—(C₁₋₆alkyl)₂amino, piperidinyl, morpholino orpiperazinyl;

R⁵ is hydrogen;

G is N;

m is 2 or 3; and

q is 0 or 1;

or a pharmaceutically acceptable salt, or an in vivo cleavable esterthereof.

An additional aspect of the present invention provides a compound of theFormula (I) (as depicted above) wherein:

R¹ is C₁₋₄alkoxy, morpholinylC₂₋₄alkoxy, pyrrolidinylC₂₋₄alkoxy orpyridylC₂₋₄alkoxy;

R² is hydrogen, methyl, fluoro or chloro;

R³ is hydrogen, methyl, fluoro or chloro;

R⁴ is hydrogen or methoxy or R⁴ is phenyl, furyl, isoxazolyl or pyridyloptionally substituted by one or more groups selected from fluoro,chloro, cyano, methyl, methoxy, N,N-dimethylamino or morpholino;

R⁵ is hydrogen;

G is N;

m is 2 or 3; and

q is 0 or 1;

or a pharmaceutically acceptable salt, or an in vivo cleavable esterthereof.

A further additional aspect of the present invention provides a compoundof the Formula (I) (as depicted above) wherein:

R¹ is methoxy, 2-morpholinoethoxy, 3-morpholinopropoxy,2-pyrrolidin-1-ylethoxy or 3-pyrid-3-ylpropoxy;

R² is hydrogen, methyl, fluoro or chloro;

R³ is hydrogen, methyl, fluoro or chloro;

R⁴ is hydrogen, methoxy, phenyl, 2-methylphenyl,3-(N,N-dimethylamino)phenyl, 3-fluorophenyl, 3-methoxyphenyl,4-cyanophenyl, 3,4-dimethoxyphenyl, 3-morpholinophenyl, 2-furyl,2-chloropyrid-5-yl, 2-morpholinopyrid-4-yl or isoxazol-5-yl;

R⁵ is hydrogen;

G is N;

m is 2 or 3; and

q is 0 or 1;

or a pharmaceutically acceptable salt, or an in vivo cleavable esterthereof.

A further additional aspect of the present invention provides a compoundof the Formula (I) (as depicted above) wherein:

R¹ is methoxy, 2-dimethylaminoethoxy, 2-diethylaminoethoxy,2-diisopropylaminoethoxy, 3-dimethylaminopropoxy, 3-diethylaminopropoxy,2-morpholinoethoxy, 3-morpholinopropoxy, 2-piperidinoethoxy,N-methylpiperidin-2-ylmethoxy, N-methylpiperidin-3-ylmethoxy,2-pyrrolidin-1-ylethoxy, 2-(N-methylpyrrolidin-2-yl)ethoxy,N-methyl-5-oxopyrrolidin-2-ylmethoxy, 3-pyrrolidin-1-ylpropoxy,2-(2-oxoimidazolidin-1-yl)ethoxy, 2-(4-methylpiperazin-1-yl)ethoxy or3-pyrid-3-ylpropoxy;

R² is hydrogen, methyl, fluoro or chloro;

R³ is hydrogen, methyl, fluoro or chloro;

R⁴ is pyridyl optionally substituted by a N,N-dimethylamino,N,-diethylamino, pyrrolidin-1-yl, piperidino or morpholino group.

R⁵ is hydrogen;

G is N;

m is 1, 2 or 3; and

q is 0;

or a pharmaceutically acceptable salt, or an in vivo cleavable esterthereof.

Preferred compounds are those of Examples 1-86 or a pharmaceuticallyacceptable salt or an in vivo cleavable ester thereof.

Especially preferred compounds are those of Examples 18, 20, 23, 26, 31,33, 34, 36, 40, 44, 45 or 48 or a pharmaceutically acceptable salt or anin vivo cleavable ester thereof.

More especially preferred compounds are those of Examples 56, 58, 60,61, 62, 63, 64, 65, 66, 68, 69 or 73 or a pharmaceutically acceptablesalt or an in vivo cleavable ester thereof.

A further especially preferred compound of the invention is, forexample:

4-(3-benzamido-4-fluoroanilino)-6,7-dimethoxyquinazoline,

6-(2-diisopropylaminoethoxy)-7-methoxy-4-[2-methyl-5-(2-morpholinopyridine-4-carboxamido)anilino]quinazoline,

6-(2-dimethylaminoethoxy)-7-methoxy4-[2-methyl-5-(2-morpholinopyridine-4-carboxamido)anilino]quinazolineor

6-(3-pyrrolidin-1-ylpropoxy)-7-methoxy-4-[2-methyl-5-(2-morpholinopyridine-4-carboxamido)anilino]quinazoline;

or a pharmaceutically acceptable salt or an in vivo cleavable esterthereof.

A further especially preferred compound of the invention is, forexample:

4-(3-benzamido-4-fluoroanilino)-6,7-dimethoxyquinoline;

or a pharmaceutically acceptable salt or an in vivo cleavable esterthereof.

A suitable pharmaceutically acceptable salt of a compound of the Formula(I) is, for example, an acid-addition salt of a compound of the Formula(I) which is sufficiently basic, for example an acid-addition salt withan inorganic or organic acid such as hydrochloric, hydrobromic,sulphuric, trifluoroacetic, citric or maleic acid; or, for example asalt of a compound of the Formula (I) which is sufficiently acidic, forexample an alkali or alkaline earth metal salt such as a calcium ormagnesium salt, or an ammonium salt, or a salt with an organic base suchas methylamine, dimethylamine, trimethylamine, piperidine, morpholine ortris-(2-hydroxyethyl)amine.

Various forms of prodrugs are known in the art. For examples of suchprodrug derivatives, see:

a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) andMethods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al.(Academic Press, 1985);

b) A Textbook of Drug Design and Development, edited byKrogsgaard-Larsen and H. Bundgaard. Chapter 5 “Design and Application ofProdrugs”, by H. Bundgaard p. 113-191 (1991);

c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992);

d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285(1988); and

e) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984).

Examples of such pro-drugs may be used to form in vivo cleavable estersof a compound of the Formula (I). An in vivo cleavable ester of acompound of the Formula (I) containing a carboxy group is, for example,a pharmaceutically-acceptable ester which is cleaved in the human oranimal body to produce the parent acid. Suitablepharmaceutically-acceptable esters for carboxy include C₁₋₆alkoxymethylesters. for example methoxymethyl; C₁₋₆alkanoyloxymethyl esters, forexample pivaloyloxymethyl; phthalidyl esters;C₃₋₈cycloalkoxycarbonyloxyC₁₋₆alkyl esters, for example1-cyclohexylcarbonyloxyethyl; 1,3-dioxolan-2-ylmethyl esters, forexample 5-methyl-1,3-dioxolan-2-ylmethyl; and C₁₋₆alkoxycarbonyloxyethylesters, for example 1-methoxycarbonyloxyethyl; and may be formed at anycarboxy group in the compounds of this invention.

In order to use a compound of the Formula (I), or a pharmaceuticallyacceptable salt or in vivo cleavable ester thereof, for the therapeutictreatment (including prophylactic treatment) of mammals includinghumans, it is normally formulated in accordance with standardpharmaceutical practice as a pharmaceutical composition.

According to this aspect of the invention there is provided apharmaceutical composition which comprises an amide derivative of theFormula (I), or a pharmaceutically acceptable salt or in vivo cleavableester thereof, as defined hereinbefore in association with apharmaceutically acceptable diluent or carrier.

The compositions of the invention may be in a form suitable for oral use(for example as tablets, lozenges, hard or soft capsules, aqueous oroily suspensions, emulsions, dispersible powders or granules, syrups orelixirs), for topical use (for example as creams, ointments, gels, oraqueous or oily solutions or suspensions), for administration byinhalation (for example as a finely divided powder or a liquid aerosol),for administration by insufflation (for example as a finely dividedpowder) or for parenteral administration (for example as a sterileaqueous or oily solution for intravenous, subcutaneous, intramuscular orintramuscular dosing or as a suppository for rectal dosing).

The compositions of the invention may be obtained by conventionalprocedures using conventional pharmaceutical excipients, well known inthe art. Thus, compositions intended for oral use may contain, forexample, one or more colouring, sweetening, flavouring and/orpreservative agents.

Suitable pharmaceutically acceptable excipients for a tablet formulationinclude, for example, inert diluents such as lactose. sodium carbonate,calcium phosphate or calcium carbonate, granulating and disintegratingagents such as corn starch or algenic acid; binding agents such asstarch; lubricating agents such as magnesium stearate, stearic acid ortalc; preservative agents such as ethyl or propyl p-hydroxybenzoate, andanti-oxidants, such as ascorbic acid. Tablet formulations may beuncoated or coated either to modify their disintegration and thesubsequent absorption of the active ingredient within thegastrointestinal tract, or to improve their stability and/or appearance,in either case, using conventional coating agents and procedures wellknown in the art.

Compositions for oral use may be in the form of hard gelatin capsules inwhich the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules in which the active ingredient is mixed with water oran oil such as peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions generally contain the active ingredient in finelypowdered form together with one or more suspending agents, such assodium carboxymethylcellulose, methylcellulose,hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone,gum tragacanth and gum acacia: dispersing or wetting agents such aslecithin or condensation products of an alkylene oxide with fatty acids(for example polyoxethylene stearate), or condensation products ofethylene oxide with long chain aliphatic alcohols, for exampleheptadecaethyleneoxycetanol, or condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol such aspolyoxyethylene sorbitol monooleate, or condensation products ofethylene oxide with partial esters derived from fatty acids and hexitolanhydrides, for example polyethylene sorbitan monooleate. The aqueoussuspensions may also contain one or more preservatives (such as ethyl orpropyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid),colouring agents, flavouring agents, and/or sweetening agents (such assucrose, saccharine or aspartame).

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil (such as arachis oil, olive oil, sesame oil orcoconut oil) or in a mineral oil (such as liquid paraffin). The oilysuspensions may also contain a thickening agent such as beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set outabove, and flavouring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water generally contain the activeingredient together with a dispersing or wetting agent, suspending agentand one or more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients such as sweetening, flavouring and colouringagents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, suchas olive oil or arachis oil, or a mineral oil, such as for exampleliquid paraffin or a mixture of any of these. Suitable emulsifyingagents may be, for example, naturally-occurring gums such as gum acaciaor gum tragacanth, naturally-occurring phosphatides such as soya bean,lecithin, an esters or partial esters derived from fatty acids andhexitol anhydrides (for example sorbitan monooleate) and condensationproducts of the said partial esters with ethylene oxide such aspolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening, flavouring and preservative agents.

Syrups and elixirs may be formulated with sweetening agents such asglycerol, propylene glycol, sorbitol, aspartame or sucrose, and may alsocontain a demulcent, preservative, flavouring and/or colouring agent.

The pharmaceutical compositions may also be in the form of a sterileinjectable aqueous or oily suspension, which may be formulated accordingto known procedures using one or more of the appropriate dispersing orwetting agents and suspending agents, which have been mentioned above. Asterile injectable preparation may also be a sterile injectable solutionor suspension in a non-toxic parentally-acceptable diluent or solvent,for example a solution in 1,3-butanediol.

Suppository formulations may be prepared by mixing the active ingredientwith a suitable non-irritating excipient which is solid at ordinarytemperatures but liquid at the rectal temperature and will thereforemelt in the rectum to release the drug. Suitable excipients include, forexample, cocoa butter and polyethylene glycols.

Topical formulations, such as creams, ointments, gels and aqueous oroily solutions or suspensions, may generally be obtained by formulatingan active ingredient with a conventional, topically acceptable, vehicleor diluent using conventional procedures well known in the art.

Compositions for administration by insufflation may be in the form of afinely divided powder containing particles of average diameter of, forexample, 30 μm or much less, the powder itself comprising either activeingredient alone or diluted with one or more physiologically acceptablecarriers such as lactose. The powder for insufflation is thenconveniently retained in a capsule containing, for example, 1 to 50 mgof active ingredient for use with a turbo-inhaler device, such as isused for insufflation of the known agent sodium cromoglycate.

Compositions for administration by inhalation may be in the form of aconventional pressurised aerosol arranged to dispense the activeingredient either as an aerosol containing finely divided solid orliquid droplets. Conventional aerosol propellants such as volatilefluorinated hydrocarbons or hydrocarbons may be used and the aerosoldevice is conveniently arranged to dispense a metered quantity of activeingredient.

For further information on Formulation the reader is referred to Chapter25.2 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch;Chairman of Editorial Board), Pergamon Press 1990.

The amount of active ingredient that is combined with one or moreexcipients to produce a single dosage form will necessarily varydepending upon the host treated and the particular route ofadministration. For example, a formulation intended for oraladministration to humans will generally contain, for example, from 0.5mg to 2 g of active agent compounded with an appropriate and convenientamount of excipients which may vary from about 5 to about 98 percent byweight of the total composition. Dosage unit forms will generallycontain about 1 mg to about 500 mg of an active ingredient. For furtherinformation on Routes of Administration and Dosage Regimes the reader isreferred to Chapter 25.3 in Volume 5 of Comprehensive MedicinalChemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press1990.

The size of the dose for therapeutic or prophylactic purposes of acompound of the Formula (I) will naturally vary according to the natureand severity of the conditions, the age and sex of the animal or patientand the route of administration, according to well known principles ofmedicine.

In using a compound of the Formula (I) for therapeutic or prophylacticpurposes it will generally be administered so that a daily dose in therange, for example, 0.5 mg to 75 mg per kg body weight, preferably 0.5mg to 40 mg per kg body weight, is received, given if required individed doses. In general lower doses will be administered when aparenteral route is employed. Thus, for example, for intravenousadministration, a dose in the range, for example, 0.5 mg to 30 mg per kgbody weight will generally be used. Similarly, for administration byinhalation, a dose in the range, for example, 0.5 mg to 25 mg per kgbody weight will be used. Oral administration is however preferred,particularly in tablet form. Typically, unit dosage forms will containabout 1 mg to 500 mg of a compound of this invention.

The compounds of this invention may be used in combination with otherdrugs and therapies used in the treatment of disease states which wouldbenefit from the inhibition of cytokines, in particular TNF and IL-1.For example, the compounds of the Formula (I) could be used incombination with drugs and therapies used in the treatment of rheumatoidarthritis, asthma, irritable bowel disease, multiple sclerosis, AIDS,septic shock, congestive heart failure, ischaemic heart disease,psoriasis and the other disease states mentioned earlier in thisspecification.

For example, by virtue of their ability to inhibit cytokines, thecompounds of the Formula (I) are of value in the treatment of certaininflammatory and non-inflammatory diseases which are currently treatedwith a cyclooxygenase-inhibitory non-steroidal anti-inflammatory drug(NSAID) such as indomethacin, ketorolac, acetylsalicylic acid,ibuprofen, sulindac, tolmetin and piroxicam. Co-administration of acompound of the Formula (I) with a NSAID can result in a reduction ofthe quantity of the latter agent needed to produce a therapeutic effect.Thereby the likelihood of adverse side-effects from the NSAID such asgastrointestinal effects are reduced. Thus according to a furtherfeature of the invention there is provided a pharmaceutical compositionwhich comprises a compound of the Formula (I), or a pharmaceuticallyacceptable salt or in vivo cleavable ester thereof, in conjunction oradmixture with a cyclooxygenase inhibitory non-steroidalanti-inflammatory agent, and a pharmaceutically acceptable diluent orcarrier.

The compounds of the invention may also be used with anti-inflammatoryagents such as an inhibitor of the enzyme 5-lipoxygenase (such as thosedisclosed in European Patent Applications Nos. 0351194, 0375368,0375404, 0375452, 0375457, 0381375, 0385662, 0385663, 0385679, 0385680).

The compounds of the Formula (I) may also be used in the treatment ofconditions such as rheumatoid arthritis in combination withantiarthritic agents such as gold, methotrexate, steroids andpenicillinamine, and in conditions such as osteoarthritis in combinationwith steroids.

The compounds of the present invention may also be administered indegradative diseases, for example osteoarthritis, withchondroprotective, anti-degradative and/or reparative agents such asDiacerhein, hyaluronic acid formulations such as Hyalan, Rumalon,Arteparon and glucosamine salts such as Antril.

The compounds of the Formula (I) may be used in the treatment of asthmain combination with antiasthmatic agents such as bronchodilators andleukotriene antagonists.

If formulated as a fixed dose such combination products employ thecompounds of this invention within the dosage range described herein andthe other pharmaceutically-active agent within its approved dosagerange. Sequential use is contemplated when a combination formulation isinappropriate.

Although the compounds of the Formula (I) are primarily of value astherapeutic agents for use in warm-blooded animals (including man), theyare also useful whenever it is required to inhibit the effects ofcytokines. Thus, they are useful as pharmacological standards for use inthe development of new biological tests and in the search for newpharmacological agents.

According to a further aspect of the present invention, there isprovided a process for preparing a compound of the Formula (I), or apharmaceutically acceptable salt or an in vivo cleavable ester thereof,which process (wherein R¹, R², R³, R⁴, R⁵, G, m and q are as defined forFormula (I) unless otherwise stated) comprises of:

a) reacting an aniline of the Formula (II):

 with an acyl compound of the Formula (III):

wherein L is a displaceable group as defined below;

b) reacting an activated heteroaryl of the Formula (IV):

wherein L is a displaceable group as defined below, with an aniline ofthe Formula (V):

or c) for the preparation of a compound of the Formula (I) wherein R¹ ora substituent on R⁴ is C₁₋₆alkoxy or substituted C₁₋₆alkoxy,C₁₋₆alkylS—, N—C₁₋₆alkylamino, N,N—(C₁₋₆alkyl)₂amino or substitutedC₁₋₆alkylamino, the alkylation, conveniently in the presence of asuitable base as defined below, of an amide derivative of the Formula(I) wherein R¹ or a substituent on R⁴ is hydroxy, mercapto or amino asappropriate;

and thereafter if necessary:

i) converting a compound of the Formula (I) into another compound of theFormula (I);

ii) removing any protecting groups; and

iii) forming a pharmaceutically acceptable salt or in vivo cleavableester.

Specific reaction conditions for the above process variants are asfollows:

For process variant a) A suitable displaceable group L is, for example,a halogeno, activated phenoxy group or sulphonyloxy group, for example achloro, bromo, pentafluorophenoxy or methanesulphonyloxy ortoluene-4-sulphonyloxy group. Especially preferred displaceable groupsare chloro and pentafluorophenoxy.

Anilines of the Formula (II) and acyl compounds of the Formula (III) maybe reacted together in a suitable inert solvent or diluent, for exampledichloromethane, acetonitrile, butanol, tetramethylene sulphone,tetrahydrofuran, 1,2-dimethoxyethane, N,N-dimethylformamide,N,N-dimethylacetamide or N-methylpyrrolidin-2-one, optionally in thepresence of a suitable base, and at a temperature in the range, forexample, 0° to 50° C., conveniently at or near room temperature.

A suitable base is, for example, an alkali or alkaline earth metalcarbonate, alkoxide, hydroxide or hydride, for example sodium carbonate,potassium carbonate, sodium ethoxide, potassium butoxide, sodiumhydroxide, potassium hydroxide, sodium hydride or potassium hydride, oran organometallic base such as an alkyl-lithium, for examplen-butyl-lithium, or a dialkylamino-lithium, for example lithiumdi-isopropylamide, or, for example, an organic amine base such as, forexample, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine,triethylamine, morpholine or diazabicyclo[5.4.0]undec-7-ene.

Anilines of the Formula (II) may be prepared by the reaction of theactivated heteroaryl of the Formula (IV) according to the followingscheme:

wherein Q is —NH₂ or, if R² and R³ are not identical and a regiospecificreaction is desired, Q can be amino protected by a suitable protectinggroup (such as those defined below) or nitro, whereafter the protectinggroup is removed, or the nitro group is reduced (for example with ironpowder and acetic acid) to generate the aniline of the Formula (II).

Activated heteroaryls of the Formula (IV) are known compounds, arecommercially available or are prepared by processes known in the art.For example where L is chloro as in Formula (IVB) or pentafluorophenoxyas in Formula (IVC), suitable compounds of the Formula (IV) may beprepared by the following scheme from compounds of the Formula (IVA)which are known compounds, are commercially available or are prepared byprocesses known in the art:

For process variant b) A suitable displaceable group L is as definedabove.

Activated heteroaryls of the formula (IV) and anilines of the Formula(V) may be reacted together in the presence of a protic solvent, forexample, isopropanol, in the presence of an acid, for example hydrogenchloride gas in diethyl ether, or hydrochloric acid, and at atemperature in the range, for example, 0° to 150° C., conveniently at ornear reflux.

Anilines of the Formula (V) are, known compounds, are commerciallyavailable, or are made by processes known in the art. For example,anilines of the Formula (V) may be prepared according to the followingscheme:

wherein Q is as defined above.

Compounds of the Formulae (IIB), (III), (VA) and (VB) are knowncompounds, are commercially available or are prepared by processes knownin the art.

For process variant c) A suitable alkylating agent is, for example, anyagent known in the art for the alkylation of hydroxy to alkoxy orsubstituted alkoxy, or for the alkylation of mercapto to alkylthio, orfor the alkylation of amino to alkylamino or substituted alkylamino, forexample an alkyl or substituted alkyl halide, for example a C₁₋₆alkylchloride, bromide or iodide or a substituted C₁₋₆alkyl chloride, bromideor iodide, in the presence of a suitable base and in a suitable inertsolvent or diluent as defined above for process variant a).

The reaction is conveniently carried out at a temperature in the range,for example, 10 to 150° C., preferably in the range 20 to 80° C.

Any necessary protecting groups may in general be chosen from any of thegroups described in the literature or known to the skilled chemist asappropriate for the protection of the group in question and may beintroduced by conventional methods. Protecting groups may be removed byany convenient method as described in the literature or known to theskilled chemist as appropriate for the removal of the protecting groupin question, such methods being chosen so as to effect removal of theprotecting group with minimum disturbance of groups elsewhere in themolecule.

Specific examples of protecting groups are given below for the sake ofconvenience, in which “lower”, as in, for example, lower alkyl,signifies that the group to which it is applied preferably has 1-4carbon atoms. It will be understood that these examples are notexhaustive. Where specific examples of methods for the removal ofprotecting groups are given below these are similarly not exhaustive.The use of protecting groups and methods of deprotection notspecifically mentioned would be available to the skilled chemist and arewithin the scope of the invention.

A carboxy protecting group may be the residue of an ester-formingaliphatic or arylaliphatic alcohol or of an ester-forming silanol (thesaid alcohol or silanol preferably containing 1-20 carbon atoms).Examples of carboxy protecting groups include esters involving straightor branched chain C₁₋₁₂alkyl groups (for example isopropyl, tert-butyl);lower alkoxy lower alkyl groups (for example methoxymethyl,ethoxymethyl, isobutoxymethyl); lower aliphatic acyloxy lower alkylgroups, (for example acetoxymethyl, propionyloxymethyl,butyryloxymethyl, pivaloyloxymethyl); lower alkoxycarbonyloxy loweralkyl groups (for example 1-methoxycarbonyloxyethyl,1-ethoxycarbonyloxyethyl); aryl lower alkyl groups (for example benzyl,p-methoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, benzhydryl andphthalidyl); tri(lower alkyl)silyl groups (for example trimethylsilyland tert-butyldimethylsilyl); tri(lower alkyl)silyl lower alkyl groups(for example trimethylsilylethyl); and C₂₋₆alkenyl groups (for exampleallyl and vinylethyl).

Methods particularly appropriate for the removal of carboxyl protectinggroups include for example acid-, base-, metal- or enzymically-catalysedhydrolysis.

Examples of hydroxy protecting groups include ethers involving loweralkyl groups (for example tert-butyl), lower alkenyl groups (for exampleallyl); lower alkanoyl groups (for example acetyl); lower alkoxycarbonylgroups (for example tert-butoxycarbonyl); lower alkenyloxycarbonylgroups (for example allyloxycarbonyl); aryl lower alkoxycarbonyl groups(for example benzoyloxycarbonyl, p-methoxybenzyloxycarbonyl,o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl); tri loweralkylsilyl groups (for example trimethylsilyl, tert-butyldimethylsilyl)and aryl lower alkyl groups (for example benzyl).

Examples of amino protecting groups include amides or amines involvingformyl, aralkyl groups (for example benzyl and substituted benzyl,p-methoxybenzyl, nitrobenzyl and 2,4-dimethoxybenzyl, andtriphenylmethyl); di-p-anisylmethyl and furylmethyl groups; loweralkoxycarbonyl (for example tert-butoxycarbonyl); loweralkenyloxycarbonyl (for example allyloxycarbonyl); aryl loweralkoxycarbonyl groups (for example benzyloxycarbonyl,p-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl,p-nitrobenzyloxycarbonyl; trialkylsilyl (for example trimethylsilyl andtert-butyldimethylsilyl); alkylidene (for example methylidene);benzylidene and substituted benzylidene groups.

Methods appropriate for removal of hydroxy and amino protecting groupsinclude, for example, acid-, base-, metal- or enzymically-catalysedhydrolysis for groups such as p-nitrobenzyloxycarbonyl, hydrogenationfor groups such as benzyl and photolytically for groups such aso-nitrobenzyloxycarbonyl.

The reader is referred to Advanced Organic Chemistry, 4th Edition, byJerry March, published by John Wiley & Sons 1992, for general guidanceon reaction conditions and reagents. The reader is referred toProtective Groups in Organic Synthesis, 2nd Edition, by Green et al.,published by John Wiley & Sons for general guidance on protectinggroups.

According to a further aspect of the present invention there is provideda compound of the Formula (I), or a pharmaceutically acceptable salt oran in vivo cleavable ester thereof as defined hereinbefore, for use in amethod of treatment of the human or animal body by therapy.

In a further aspect of the present invention there is provided acompound of the Formula (I), or a pharmaceutically acceptable salt or anin vivo cleavable ester thereof as defined hereinbefore, for use as amedicament.

In a further aspect the present invention provides the use of a compoundof the Formula (I), or a pharmaceutically acceptable salt or an in vivocleavable ester thereof as defined hereinbefore, in the manufacture of amedicament for use in the treatment of diseases or medical conditionsmediated by cytokines.

In a further aspect the present invention provides a method of treatingdiseases or medical conditions mediated by cytokines which comprisesadministering to a warm-blooded animal an effective amount of a compoundof the Formula (I), or a pharmaceutically acceptable salt or an in vivocleavable ester thereof as defined hereinbefore.

In a further aspect the present invention provides the use of a compoundof the Formula (I), or a pharmaceutically acceptable salt or an in vivocleavable ester thereof as defined hereinbefore, in the manufacture of amedicament for use in the treatment of diseases or medical conditionsmediated by TNF, IL-1, IL-6 or IL-8.

In a further aspect the present invention provides a method of treatingdiseases or medical conditions mediated by TNF, IL-1, IL-6 or IL-8 whichcomprises administering to a warm-blooded animal an effective amount ofa compound of the Formula (I), or a pharmaceutically acceptable salt oran in vivo cleavable ester thereof as defined hereinbefore.

In a further aspect the present invention provides the use of a compoundof the Formula (I), or a pharmaceutically acceptable salt or an in vivocleavable ester thereof as defined hereinbefore, in the manufacture of amedicament for use in the treatment of diseases or medical conditionsmediated by TNF.

In a further aspect the present invention provides a method of treatingdiseases or medical conditions mediated by TNF which comprisesadministering to a warm-blooded animal an effective amount of a compoundof the Formula (I), or a pharmaceutically acceptable salt or an in vivocleavable ester thereof as defined hereinbefore.

In a further aspect the present invention provides the use of a compoundof the Formula (I), or a pharmaceutically acceptable salt or an in vivocleavable ester thereof as defined hereinbefore, in the manufacture of amedicament for use in inhibiting TNF, IL-1, IL-6 or IL-8.

In a further aspect the present invention provides a method ofinhibiting TNF, IL-1, IL-6 or IL-8 which comprises administering to awarm-blooded animal an effective amount of a compound of the Formula(I), or a pharmaceutically acceptable salt or an in vivo cleavable esterthereof as defined hereinbefore.

In a further aspect the present invention provides the use of a compoundof the Formula (I), or a pharmaceutically acceptable salt or an in vivocleavable ester thereof as defined hereinbefore, in the manufacture of amedicament for use in inhibiting TNF.

In a further aspect the present invention provides a method ofinhibiting TNF which comprises administering to a warm-blooded animal aneffective amount of a compound of the Formula (I), or a pharmaceuticallyacceptable salt or an in vivo cleavable ester thereof as definedhereinbefore.

In a further aspect the present invention provides the use of a compoundof the Formula (I), or a pharmaceutically acceptable salt or an in vivocleavable ester thereof as defined hereinbefore, in the manufacture of amedicament for use in the treatment of diseases or medical conditionsmediated by p38 kinase.

In a further aspect the present invention provides a method of treatingdiseases or medical conditions mediated by p38 kinase which comprisesadministering to a warm-blooded animal an effective amount of a compoundof the Formula (I), or a pharmaceutically acceptable salt or an in vivocleavable ester thereof as defined hereinbefore.

In a further aspect the present invention provides the use of a compoundof the Formula (I), or a pharmaceutically acceptable salt or an in vivocleavable ester thereof as defined hereinbefore, in the manufacture of amedicament for use in the production of a p38 kinase inhibitory effect.

In a further aspect the present invention provides a method of providinga p38 kinase inhibitory effect which comprises administering to awarm-blooded animal an effective amount of a compound of the Formula(I), or a pharmaceutically acceptable salt or an in vivo cleavable esterthereof as defined hereinbefore.

In a further aspect the present invention provides the use of a compoundof the Formula (I), or a pharmaceutically acceptable salt or an in vivocleavable ester thereof as defined hereinbefore, in the manufacture of amedicament for use in the treatment of rheumatoid arthritis, asthma,irritable bowel disease, multiple sclerosis, AIDS, septic shock,congestive heart failure, ischaemic heart disease or psoriasis.

In a further aspect the present invention provides a method of treatingrheumatoid arthritis, asthma, irritable bowel disease, multiplesclerosis, AIDS, septic shock, congestive heart failure, ischaemic heartdisease or psoriasis which comprises administering to a warm-bloodedanimal an effective amount of a compound of the Formula (I), or apharmaceutically acceptable salt or an in vivo cleavable ester thereofas defined hereinbefore.

The following biological assays and Examples serve to illustrate thepresent invention.

Biological Assays

The following assays can be used to measure the p38 kinase-inhibitory,the TNF-inhibitory and anti-arthritic effects of the compounds of thepresent invention:

In vitro Enzyme Assay

The ability of compounds of the invention to inhibit the enzyme p38kinase was assessed. Activity of particular test compounds against eachof the p38α and p38β isoforms of the enzyme was determined.

Human recombinant MKK6 (GenBank Accesion Number G1209672) was isolatedfrom Image clone 45578 (Genomics, 1996, 33, 151) and utilised to produceprotein in the form of a GST fusion protein in a pGEX vector usinganalogous procedures to those disclosed by J. Han et al., Journal ofBiological Chemistry, 1996, 271, 2886-2891. p38α (GenBank AccessionNumber G529039) and p38β (GenBank Accession Number G1469305) wereisolated by PCR amplification of human lymphoblastoid cDNA (GenBankAccession Number GM1416) and human foetal brain cDNA [synthesised frommRNA (Clontech, catalogue no. 6525-1) using a Gibco superscript cDNAsynthesis kit] respectively using oligonucleotides designed for the 5′and 3′ ends of the human p38α and p38β genes using analogous proceduresto those described by J. Han et al., Biochimica et Biophysica Acta,1995, 1265, 224-227 and Y. Jiang et al., Journal of BiologicalChemistry, 1996, 271, 17920-17926.

Both p38 protein isoforms were expressed in e coli in PET vectors. Humanrecombinant p38α and p38β isoforms were produced as 5′ c-myc, 6Histagged proteins. Both MKK6 and the p38 proteins were purified usingstandard protocols: the GST MKK6 was purified using a glutathionesepharose column and the p38 proteins were purified using nickel chelatecolumns.

The p38 enzymes were activated prior to use by incubation with MKK6 for3 hours at 30° C. The unactivated coli-expressed MKK6 retainedsufficient activity to fully activate both isoforms of p38. Theactivation incubate comprised p38α (10 μl of 10 mg/ml) or p38β (10 μl of5 mg/ml) together with MKK6 (10 μl of 1 mg/ml), ‘Kinase buffer’ [100 μl;pH 7.4 buffer comprising Tris (50 mM), EGTA (0.1 mM), sodiumorthovanadate (0.1 mM) and β-mercaptoethanol (0.1%)] and MgATP (30 μl of50 mM Mg(OCOCH₃)₂ and 0.5 mM ATP). This produced enough activated p38enzyme for 3 Microtiter plates.

Test compounds were solubilised in DMSO and 10 μl of a 1:10 dilutedsample in ‘Kinase Buffer’ was added to a well in a Microtiter plate. Forsingle dose testing, the compounds were tested at 10 μM. ‘Kinase AssayMix’ [30 μl; comprising Myelin Basic Protein (Gibco BRL cat. no.1322B-010; 1 ml of a 3.33 mg/ml solution in water), activated p38 enzyme(50 μl) and ‘Kinase Buffer’ (2 ml)] was then added followed by ‘LabelledATP’ [10 μl; comprising 50 μM ATP, 0.1 μCi ³³P ATP (AmershamInternational cat. no. BF1000) and 50 mM Mg(OCOCH₃)₂]. The plates wereincubated at room temperature with gentle agitation. Plates containingp38α were incubated for 90 min and plates containing p38β were incubatedfor 45 min. Incubation was stopped by the addition of 50 μl of 20%trichloroacetic acid (TCA). The precipitated protein was phosphorylatedby p38 kinase and test compounds were assessed for their ability toinhibit this phosphorylation. The plates were filtered using a CanberraPackard Unifilter and washed with 2% TCA, dried overnight and counted ona Top Count scintillation counter.

Test compounds were tested initially at a single dose and activecompounds were retested to allow IC₅₀ values to be determined.

In vitro Cell-based Assays

(i) PBMC

The ability of compounds of this invention to inhibit TNFα productionwas assessed by using human peripheral blood mononuclear cells whichsynthesise and secrete TNFα when stimulated with lipopolysaccharide.

Peripheral blood mononuclear cells (PBMC) were isolated from heparinised(10 units/ml heparin) human blood by density centrifugation(Lymphoprep™; Nycomed). Mononuclear cells were resuspended in culturemedium [RPMI 1640 medium (Gibco) supplemented with 50 units/mlpenicillin, 50 μg/ml streptomycin, 2 mM glutamine and 1%heat-inactivated human AB serum (Sigma H-1513)]. Compounds weresolubilised in DMSO at a concentration of 50 mM, diluted 1:100 inculture medium and subsequently serial dilutions were made in culturemedium containing 1% DMSO. PBMCs (2.4×10⁵ cells in 160 μl culturemedium) were incubated with 20 μl of varying concentrations of testcompound (triplicate cultures) or 20 μl culture medium containing 1%DMSO (control wells) for 30 minutes at 37° C. in a humidified (5%CO₂/95%air) incubator (Falcon 3072; 96 well flat-bottom tissue culture plates).20 μl lipopolysaccharide [LPS E.Coli 0111:B4 (Sigma L-4130), finalconcentration 10 μg/ml] solubilised in culture medium was added toappropriate wells. 20 μl culture medium was added to “medium alone”control wells. Six “LPS alone” and four “medium alone” controls wereincluded on each 96 well plate. Varying concentrations of a known TNFαinhibitor were included in each test, i.e. an inhibitor of the PDE TypeIV enzyme (for example see Semmler, J. Wachtel. H and Endres, S., Int.J. Immunopharmac. (1993), 15(3), 409-413) or an inhibitor of pro TNFαconvertase (for example, see McGeehan, G. M. et al. Nature (1994) 370,558-561). Plates were incubated for 7 hours at 37° C. (humidifiedincubator) after which 100 μl of the supernatant was removed from eachwell and stored at −70° C. (96 well round-bottom plates; Corning 25850).TNFα levels were determined in each sample using a human TNFα ELISA (seeWO92/10190 and Current Protocols in Molecular Biology, vol 2 byFrederick M. Ausbel et al., John Wiley and Sons Inc.).

% inhibition=(LPS alone−medium alone)−(test concentration−mediumalone)/(LPS alone−medium alone)×100

(ii) Human Whole Blood

The ability of the compounds of this invention to inhibit TNFαproduction was also assessed in a human whole blood assay. Human wholeblood secretes TNFα when stimulated with LPS. This property of bloodforms the basis of an assay which is used as a secondary test forcompounds which profile as active in the PBMC test.

Heparinised (10 units/ml) human blood was obtained from volunteers. 160μl whole blood were added to 96 well round-bottom plates (Corning25850). Compounds were solubilised and serially diluted in RPMI 1640medium (Gibco) supplemented with 50 units/ml penicillin, 50 μg/mlstreptomycin and 2 mM glutamine, as detailed above. 20 μl of each testconcentration was added to appropriate wells (triplicate cultures). 20μl of RPMI 1640 medium supplemented with antibiotics and glutamine wasadded to control wells. Plates were incubated for 30 minutes at 37° C.(humidified incubator), prior to addition of 20 μl LPS (finalconcentration 10 μg/ml). RPMI 1640 medium was added to control wells.Six “LPS alone” and four “medium alone” controls were included on eachplate. A known TNFα synthesis/secretion inhibitor was included in eachtest. Plates were incubated for 6 hours at 37° C. (humidifiedincubator). Plates were centrifuged (2000 rpm for 10 minutes) and 100 μlplasma removed and stored at −70° C. (Corning 25850 plates). TNFα levelswere measured by ELISA (see WO92/10190 and Current Protocols inMolecular Biology, vol 2 by Frederick M. Ausbel et al., John Wiley andSons Inc.). The paired antibodies that were used in the ELIZA wereobtained from R&D Systems (catalogue nos. MAB610 anti-human TNFα coatingantibody, BAF210 biotinylated anti-human TNFα detect antibody).

Ex vivo/In vivo Assessment

The ability of the compounds of this invention as ex vivo TNFαinhibitors were assessed in the rat or mouse. Briefly, groups of maleWistar Alderley Park (AP) rats (180-210 g) were dosed with compound (6rats) or drug vehicle (10 rats) by the appropriate route, for exampleperoral (p.o.), intraperitoneal (i.p.) or subcutaneous (s.c.). Ninetyminutes later rats were sacrificed using a rising concentration of CO₂and bled out via the posterior vena cavae into 5 Units of sodiumheparin/ml blood. Blood samples were immediately placed on ice andcentrifuged at 2000 rpm for 10 min at 4° C. and the harvested plasmasfrozen at −20° C. for subsequent assay of their effect on TNFαproduction by LPS-stimulated human blood. The rat plasma samples werethawed and 175 μl of each sample was added to a set format pattern in a96 well round bottom plate (Corning 25850). 50 μl of heparinized humanblood was then added to each well, mixed and the plate was incubated for30 min at 37° C. (humidified incubator). LPS (25 μl; final concentration10 μg/ml) was added to the wells and incubation continued for a further5.5 hours. Control wells were incubated with 25 μl of medium alone.Plates were then centrifuged for 10 min at 2000 rpm and 200 μl of thesupernatants were transferred to a 96 well plate and frozen at −20° C.for subsequent analysis of TNF concentration by ELISA.

Data analysis by dedicated software calculates for each compound/dose:

% inhibition of TNFα=Mean TNFα (Controls)−Mean TNFα (Treated)/Mean TNFα(Controls)×100

Alternatively, mice could be used instead of rats in the aboveprocedure.

Test as Anti-arthritic Agent

Activity of a compound as an anti-arthritic agent was tested as follows.Acid soluble native type II collagen was shown by Trentham et al. [1] tobe arthritogenic in rats; it caused polyarthritis when administered inFreunds incomplete adjuvant. This is now known as collagen-inducedarthritis (CIA) and similar conditions can be induced in mice andprimates. Recent studies have shown that anti-TNF monoclonal antibodies[2] and TNF receptor-IgG fusion proteins [3] ameliorate established CIAindicating that TNF plays a key role in the pathophysiology of CIA.Moreover, the remarkable efficacy reported for anti-TNF monoclonalantibodies in recent rheumatoid arthritis clinical trials indicates thatTNF plays a major role in this chronic inflammatory disease. Thus CIA inDBA/1 mice as described in references 2 and 3 is a tertiary model whichcan be used to demonstrate the anti-arthritic activity of a compound.Also see reference 4.

1. Trentham, D. E. et al., (1977) J. Exp. Med., 146, 857.

2. Williams, R. O. et al., (1992) Proc. Natl. Acad. Sci., 89, 9784.

3. Williams, R. O. et al., (1995) Immunology, 84, 433.

4. Badger, M. B. et al., (1996) The Journal of Pharmacology andExperimental Therapeutics, 279, 1453-1461.

Although the pharmacological properties of the compounds of the Formula(I) vary with structural change as expected, in general a compound ofthe Formula (I) gives over 30% inhibition of p38α and/or p38β atconcentrations up to 10 μM and over 30% inhibition in the PBMC test atconcentrations up to 50 μM. No physiologically unacceptable toxicity wasobserved at the effective dose for compounds tested of the presentinvention. By way of example:

Example IC₅₀ (p38α) IC₅₀ (PBMC) 11 1.3 3.6 14 3.4 3.2 24 0.2 5.2 38 0.12

EXAMPLES

The invention will now be illustrated in the following non-limitingExamples in which, unless otherwise stated:

(i) operations were carried out at ambient temperature, i.e. in therange 17 to 25° C. and under an atmosphere of an inert gas such as argonunless otherwise stated;

(ii) evaporations were carried out by rotary evaporation in vacuo andwork-up procedures were carried out after removal of residual solids byfiltration;

(iii) column chromatography (by the flash procedure) was performed onMerck Kieselgel silica (Art. 9385) or Merck Lichroprep RP-18 (Art. 9303)reversed-phase silica obtained from E. Merck, Darmstadt, Germany, orhigh pressure liquid chromatography (HPLC) was performed on C18reversed-phase silica, for example on a Dynamax C-18 60 Å preparativereversed-phase column;

(iv) yields where present are given for illustration only and are notnecessarily the maximum attainable;

(v) in general, the end-products of the Formula (I) have satisfactorymicroanalyses and their structures were confirmed by nuclear magneticresonance (NMR) and/or mass spectral techniques; fast-atom bombardment(FAB) mass spectral data were obtained using a Platform spectrometerand, where appropriate, either positive ion data or negative ion datawere collected; NMR chemical shift values were measured on the deltascale [proton magnetic resonance spectra were determined using a VarianGemini 2000 spectrometer operating at a field strength of 300 MHz or aBruker AM250 spectrometer operating at a field strength of 250 MHz]; thefollowing abbreviations have been used: s, singlet; d, doublet; t,triplet; m, multiplet; br, broad; unless otherwise stated deuterateddimethyl sulphoxide (DMSO-d₆) was the solvent used;

(vi) intermediates were not generally fully characterised and purity wasassessed by thin layer chromatographic, HPLC, infra-red (IR) and/or NMRanalysis;

(vii) melting points are uncorrected and were determined using a MettlerSP62 automatic melting point apparatus or an oil-bath apparatus; meltingpoints for the end-products of the Formula I were determined aftercrystallisation from a conventional organic solvent such as ethanol,methanol, acetone, ether or hexane, alone or in admixture; and

(viii) the following abbreviations have been used:

DMF N,N-dimethylformamide DMSO dimethylsulphoxide DMAN,N-dimethylacetamide. THF tetrahydrofuran

Example 1 4-[3-(3-Methoxybenzamido)anilino]-6,7-dimethoxyquinazolinehydrochloride

3-Methoxybenzoyl chloride (0.169 ml) was added to a suspension of4-(3-aminoanilino)-6,7-dimethoxyquinazoline (300 mg) in dry methylenechloride (10 ml). The reaction was stirred at ambient temperature for 18hours. The precipitated solid was isolated, washed with methylenechloride and diethyl ether and then dried under vacuum to yield thetitle compound (398 mg, 85%); NMR: 3.84 (s, 3H), 3.98 (s, 3H), 4.02 (s,3H), 7.15 (m, 1H), 7.35 (s, 1H), 7.4-7.56 (m, 5H), 7.66 (m, 1H), 8.21(s, 1H), 8.31 (s, 1H), 8.8 (s, 1H), 10.41 (s, 1H), 11.38 (s, 1H); m/s:M+H⁺ 431.

The 4-(3-aminoanilino)-6,7-dimethoxyquinazoline used as a startingmaterial was prepared as follows:

A mixture of 4,5-dimethoxyanthranilic acid (19.7 g) and formamide (10ml) was stirred and heated to 190° C. for 5 hours. The mixture wasallowed to cool to approximately 80° C. and water (50 ml) was added. Themixture was stored at ambient temperature for 3 hours. The precipitatewas isolated, washed with water and dried to give6,7-dimethoxy-3,4-dihydroquinazolin-4-one (3.65 g).

A mixture of 6,7-dimethoxy-3,4-dihydroquinazolin-4-one (2.06 g), thionylchloride (20 ml) and DMF (1 drop) was stirred and heated to reflux for 2hours. The mixture was evaporated and the residue was partitionedbetween ethyl acetate and a saturated aqueous sodium hydrogen carbonatesolution. The organic phase was washed with water, dried over magnesiumsulphate, filtered and evaporated to dryness. The residue was purifiedby column chromatography using increasingly polar mixtures of methylenechloride and ethyl acetate as the eluant to give4-chloro-6,7-dimethoxyquinazoline (0.6 g, 27%).

3-Aminoaniline (4.79 g) was added to a suspension of4-chloro-6,7-dimethoxyquinazoline (1.99 g) in isopropanol (100 ml). A 1Msolution of hydrogen chloride in diethyl ether (8.86 ml) was added andthe reaction mixture was stirred and heated to 90° C. for 3 hours. Themixture was cooled to ambient temperature and the precipitated solid wasisolated, washed with isohexane and diethyl ether and then dried undervacuum. The resulting solid was then stirred with 1M aqueous sodiumhydroxide solution and the mixture was extracted with methylenechloride. The methylene chloride extract was evaporated to dryness.There was thus obtained the required starting material (1.07 g, 41%);NMR: 3.91 (s, 3H), 3.93 (s, 3H), 5.03 (s, 2H), 6.31 (d, 1H), 6.87 (d,1H), 7.00 (m, 2H), 7.13 (s, 1H), 7.81 (s, 1H), 8.39 (s, 1H), 9.20 (s,1H); m/s: M+H⁺ 297.

Example 24-[4-Chloro-3-(3,4dimethoxybenzamido)anilino]-6,7-dimethoxyquinazolinehydrochloride

3,4-Dimethoxybenzoyl chloride (200 mg) and triethylamine (0.125 ml) wereadded to a suspension of4-(3-amino-4-chloroanilino)-6,7-dimethoxyquinazoline (150 mg) in drymethylene chloride (3 ml) and the mixture was stirred at ambienttemperature for 18 hours. The reaction mixture was diluted withmethylene chloride and washed with water and brine and evaporated. Theresidue was triturated with diethyl ether (3×100 ml). The resultingsolid was stirred in ethereal hydrogen chloride at ambient temperaturefor 18 hours and the mixture was evaporated to dryness. The resultingsolid was triturated with isohexane and dried under vacuum. The titlecompound was obtained as a solid (30 mg); NMR: 3.85 (s, 6H), 3.92 (s,3H), 3.96 (s, 3H), 6.98 (m, 1H), 7.32 (s, 1H), 7.45 (m, 2H), 7.65 (m,2H), 7.99 (m, 1H), 8.15 (s, 1H), 8.88 (s, 1H), 9.98 (s, 1H), 11.32 (s,1H); m/s: M+H⁺ 495, 497.

The 4-(3-amino-4-chloroanilino)-6,7-dimethoxyquinazoline used as astarting material was prepared as follows:

Concentrated hydrochloric acid (2.5 ml) was added to a mixture of4-chloro-6,7-dimethoxyquinazoline (3.0 g) and 4-chloro-3-nitroaniline(2.54 g) in isopropanol (100 ml) and stirred and heated to 85° C. for 18hours. After cooling the precipitated solid was isolated and washed withisohexane and diethyl ether. There was thus obtained4-(4-chloro-3-nitroanilino)-6,7-dimethoxyquinazoline hydrochloride as asolid (4.65 g, 87%); NMR: 3.99 (s, 3H), 4.06 (s, 3H), 7.38 (m, 1H), 7.85(m, 1H), 8.22 (m, 1H), 8.49 (m, 1H), 8.63 (m, 1H), 8.92 (m, 1H), 11.83(s, 1H); m/s: M+H⁺ 361, 363.

Iron powder (3.39 g) was added to a stirred mixture of4-(4-chloro-3-nitroanilino)-6,7-dimethoxyquinazoline hydrochloride (4.37g) in water (200 ml) and glacial acetic acid (2 ml) and heated to 110°C. for 4.5 hours. After cooling ethyl acetate (200 ml) was added and themixture was filtered through diatomaceous earth (Celite®). The organiclayer was separated and evaporated to dryness. This solid waspartitioned between methylene chloride and water. The organic layer wasthen washed with brine dried over sodium sulphate, filtered andevaporated to dryness to yield the required starting material (1.15 g,29%); NMR: 3.91 (s, 3H), 3.93 (s, 3H), 5.32 (s, 2H), 6.95 (m, 1H), 7.15(m, 2H), 7.3 (m, 1H), 7.8 (s, 1H), 8.42 (s, 1H); 9.28 (s, 1H); m/s: M+H⁺331, 333.

Example 34-(2-Fluoro-4-chloro-5-benzamidoanilino)-6,7-dimethoxyquinazolinehydrochloride

Benzoyl chloride (0.025 ml) and pyridine (0.036 ml) were added to asuspension of4-(5-amino-4-chloro-2-fluoroanilino)-6,7-dimethoxyquinazoline (125 mg)in dry methylene chloride (3 ml) and the resulting mixture was stirredat ambient temperature for 18 hours. Isohexane (3 ml) was added and theprecipitated solid was isolated, washed with diethyl ether and driedunder vacuum. The title compound was obtained as a solid (65 mg); NMR:4.0 (s, 6H), 7.35 (s, 1H), 7.56 (m, 3H), 7.78 (d, 2H), 7.99 (d, 2H),8.22 (s, 1H), 8.81 (s, 1H), 10.2 (broad s, 1H); m/s: M+H⁺ 453, 455.

The 4-(5-amino-4-chloro-2-fluoroanilino)-6,7-dimethoxyquinazoline usedas a starting material was prepared as follows:

Phthalic anhydride (11.83 g) was added to a solution of2-chloro-4-fluoroaniline (11.08 g) in glacial acetic acid (150 ml). Theresulting mixture was heated to 100° C. for 2 hours then allowed tocool. The precipitated solid was isolated, washed with water and driedunder vacuum. The solid thus obtained was suspended in sulphuric acid(30 ml) and a mixture of nitric acid (4.6 ml) and sulphuric acid (5 ml)was added gradually with cooling in an ice-water bath, such that theinternal reaction temperature did not exceed 30° C. The resulting clearsolution was stirred at ambient temperature for 1 hour. Ice-water (250ml) was added and the precipitated solid was isolated and dried undervacuum. There was thus obtainedN-(2-chloro-4-fluoro-5-nitrophenyl)phthalimide as a solid (17.9 g, 73%);NMR: (CDCl₃): 7.58 (d, 1H), 7.88 (m, 2H), 8.01 (m, 2H), 8.16 (d, 1H);m/s: [M−H]⁻ 319, 321.

A mixture of ethanol (450 ml), water (65 ml) and acetic acid (6.5 ml)was heated to 50° C. with stirring. Iron powder (9.0 g) was addedfollowed by N-(2-chloro-4-fluoro-5-nitrophenyl)phthalimide (8.98 g)portionwise over 10 minutes. The resulting mixture was stirred andheated to reflux for 2 hours. After cooling, solid sodium carbonate wasadded with stirring until effervescence ceased. The resulting mixturewas filtered through diatomaceous earth (Celite®) washing with ethanol.The filtrate was evaporated and the residue partitioned betweenmethylene chloride and saturated aqueous sodium bicarbonate solution.The organic extract was washed with brine, dried over sodiun sulphate,filtered and evaporated to dryness. There was thus obtainedN-(5-amino-2-chloro-4-fluorophenyl)phthalimide as a solid; NMR (CDCl₃):3.87 (s, 2H), 6.74 (d, 1H), 7.2 (d, 1H), 7.81 (m, 2H), 7.96 (m, 2H);m/s: [M−H]⁻ 289, 291.

N-(5-Amino-2-chloro-4-fluorophenyl)phthalimide (957 mg) was added to asuspension of 4-chloro-6,7-dimethoxyquinazoline (674 mg) in isopropanol(25 ml). A 1M solution of hydrogen chloride in diethyl ether (3.0 ml)was added and the reaction mixture stirred and heated to 85° C. for 3hours. After cooling the precipitated solid was isolated and washed withisohexane and diethyl ether. There was thus obtained4-(4-chloro-2-fluoro-5-phthalimidoanilino)-6,7-dimethoxyquinazolinehydrochloride as a solid (1.21 g, 84%); NMR: 4.0 (s, 6H), 7.35 (s, 1H),7.9 (d, 1H), 7.96 (m, 3H), 8.02 (m, 2H), 8.19 (s, 1H), 8.96 (s, 1H);m/s: M+H⁺ 479, 481.

4-(4-Chloro-2-fluoro-5-phthalimidoanilino)-6,7-dimethoxyquinazolinehydrochloride (1.06 g) was dissolved in ethanolamine (10 ml) and theresulting mixture was stirred at ambient temperature for 20 minutes. Themixture was dissolved in methylene chloride (200 ml) and the resultingsolution washed with water and brine, dried over sodium sulphate,filtered and evaporated to dryness. There was thus obtained4-(5-amino-4-chloro-2-fluoroanilino)-6,7-dimethoxyquinazoline as a solid(701 mg, 91%); NMR: 3.96 (s, 6H), 5.23 (s, 2H), 6.94 (d, 1H), 7.17 (s,1H), 7.23 (d, 1H), 7.76 (s, 1H), 8.33 (s, 1H), 9.33 (s, 1H); m/s: M+H⁺349, 351.

Examples 4-23

Using an analogous procedure to that described in Example 1, theappropriate acyl chloride was reacted with the appropriate aniline togive, unless otherwise stated in the appropriate footnote, thehydrochloride salt of each compound described in the following table.

Example No. R² R³ R⁴ Note  4 H H 3-fluorophenyl a)  5 H H 2-tolyl b)  6H F phenyl c)  7 H F 4-cyanophenyl d)  8 H F 3-dimethylaminophenyl e)  9H Cl 4-cyanophenyl f) 10 H Cl 3-dimethylaminophenyl g) 11 H Me phenyl h)12 F Cl 3-dimethylaminophenyl i) 13 H F methyl j) 14 H F ethyl k) 15 HCl methyl l) 16 H Cl ethyl m) 17 F Cl methyl n) 18 H F methoxymethyl o)19 H Cl methoxymethyl p) 20 F Cl 4-cyanophenyl q) 21 H H 2-furyl r) 22 HH 6-chloropyrid-3-yl s) 23 Me H 5-isoxazolyl t)

Notes

a) The product gave the following data: NMR: 3.98 (s, 3H), 4.02 (s, 3H),7.35 (s, 1H), 7.45 (m, 3H), 7.6 (m, 2H), 7.83 (m, 2H) 8.21 (s, 1H), 8.31(s, 1H), 8.8 (s, 1H), 10.52 (s, 1H), 11.36 (s, 1H); Mass: M+H⁺ 419.

b) The product gave the following data: NMR: 2.38 (s, 3H), 3.99 (s, 3H),4.01 (s, 3H), 7.28 (m, 2H), 7.35-7.48 (m, 5H), 7.55 (m, 1H), 8.17 (s,1H), 8.28 (s, 1H), 8.78 (s, 1H), 10.46 (s, 1H); Mass: M+H⁺ 415.

c) The product gave the following data: NMR: 3.95 (s, 3H), 4.0 (s, 3H),7.35-7.65 (m, 6H), 8.0 (m, 3H), 8.35 (s, 1H), 9.02 (s, 1H), 10.26 (s,1H), 11.51 (s, 1H); Mass: M+H⁺ 419.

The 4-(3-amino-4-fluoroanilino)-6,7-dimethoxyquinazoline used as astarting material was prepared as follows:

Using analogous procedures to those described in the portion of Example2 which is concerned with the preparation of starting materials,4-chloro-6,7-dimethoxyquinazoline was reacted with4-fluoro-3-nitroaniline to give4-(4-fluoro-3-nitroanilino)-6,7-dimethoxyquinazoline hydrochloride; NMR:3.98 (s, 3H), 4.03 (s, 3H), 7.39 (m, 1H), 7.7 (m, 1H), 8.25 (m, 1H),8.44 (m, 1H), 8.62 (m, 1H), 8.9 (m, 1H), 11.85 (s, 1H); Mass: M+H⁺ 345and that material was reduced during 1.5 hours to give4-(3-amino-4-fluoroanilino)-6,7-dimethoxyquinazoline; NMR: 3.9 (s, 3H),3.92 (s, 3H), 5.11 (s, 2H), 6.84 (m, 1H), 6.96 (m, 1H), 7.12 (s, 1H),7.18 (s, 1H), 7.79 (s, 1H), 8.39 (s, 1H); 9.22 (s, 1H); Mass: M+H⁺ 315.

d) The product gave the following data: NMR: 3.99 (s, 3H),4.01 (s, 3H),7.36 (s, 1H), 7.42 (m, 1H), 7.61 (m, 1H), 8.0 (m, 3H), 8.14 (m, 2H),8.36 (s, 1H), 8.81 (s, 1H), 10.57 (s, 1H), 11.54 (s, 1H); Mass: M+H⁺444.

e) The product was obtained as a dihydrochloride salt and gave thefollowing data: NMR: (DMSOd₆+CD₃CO₂D): 3.04 (s, 6H), 3.98 (s, 3H), 4.0(s, 3H), 7.36 (s, 1H), 7.25-7.5 (m, 3H), 7.55 (m, 1H), 7.67 (m, 1H), 8.0(m, 1H), 8.23 (s, 1H), 8.8 (s, 1H); Mass: M+H⁺ 462.

f) The product gave the following data: NMR: 3.98 (s, 3H),4.0 (s, 3H),7.38 (s, 1H), 7.66 (m, 1H), 7.75 (m, 1H), 8.02 (m, 3H), 8.14 (m, 2H),8.38 (s, 1H), 8.85 (s, 1H), 10.5 (s, 1H), 11.55 (s, 1H); Mass: M+H⁺ 460& 462.

g) The product was obtained as a dihydrochloride salt and gave thefollowing data: NMR: (DMSOd₆+CD₃CO₂D): 3.05 (s, 6H), 3.97 (s, 3H), 3.99(s, 3H), 7.25-7.8 (m, 7H), 8.04 (m, 1H), 8.31 (m, 1H), 8.85 (s, 1H);Mass: M+H⁺ 478 & 480.

h) The product gave the following data: NMR: 2.14 (s, 3H), 3.98 (s, 3H),4.0 (s, 3H), 7.36 (m, 2H), 7.52 (m, 4H), 7.73 (m, 1H), 7.99 (m, 2H),8.31 (s, 1H), 8.79 (s, 1H), 9.98 (s, 1H), 11.38 (s, 1H); Mass: M+H⁺ 415.

The 4-(3-amino-4-methylanilino)-6,7-dimethoxyquinazoline used as astarting material was prepared as follows:

Using analogous procedures to those described in the portion of Example2 which is concerned with the preparation of starting materials,4-chloro-6,7-dimethoxyquinazoline was reacted with4-methyl-3-nitroaniline to give4-(4-methyl-3-nitroanilino)-6,7-dimethoxyquinazoline hydrochloride; NMR:2.54 (s, 3H), 3.98 (s, 3H), 4.02 (s, 3H), 7.38 (s, 1H), 7.58 (m, 1H),8.06 (m, 1H), 8.43 (m, 2H), 8.89 (s, 1H), 11.72 (s, 1H); Mass: M+H⁺ 341and that material was reduced during 5 hours to give4-(3-amino-4-methylanilino)-6,7-dimethoxyquinazoline; NMR: 2.04 (s, 3H),3.9 (s, 3H), 3.92 (s, 3H), 4.88 (s, 2H), 6.8 (m, 1H), 6.9 (m, 1H), 7.03(s, 1H), 7.12 (m, 1H), 7.8 (s, 1H), 8.38 (s, 1H); 9.2 (s, 1H); Mass:M+H⁺ 311.

i) The product was obtained as a dihydrochloride salt and gave thefollowing data: NMR: 2.99 (s, 6H), 4.0 (s, 6H), 7.4 (m, 5H), 7.76 (m,2H), 8.4 (s, 1H), 8.84 (s, 1H), 10.22 (s, 1H), 11.89 (s, 1H); Mass: M+H⁺496 & 498.

j) The product gave the following data: NMR: 2.1 (s, 3H), 3.98 (s, 3H),4.0 (s, 3H), 7.32 (m, 2H), 7.42 (m, 1H), 8.0 (m, 1H), 8.26 (s, 1H), 8.99(s, 1H), 9.88 (s, 1H), 11.36 (s, 1H); Mass: M+H⁺ 357.

k) The product gave the following data: NMR: 1.05 (t, 3H), 2.4 (q, 2H),3.97 (s, 3H), 3.99 (s, 3H), 7.35 (m, 2H), 7.42 (m, 1H), 8.2 (m, 1H), 8.3(s, 1H), 8.79 (s, 1H), 9.78 (s, 1H), 11.41 (s, 1H); Mass: M+H⁺ 371.

l) The product gave the following data: NMR: 2.10 (s, 3H), 3.99 (s, 3H),3.97 (s, 3H), 7.34 (m, 1H), 7.58 (m, 2H), 8.07 (m, 1H), 8.27 (s, 1H),8.81 (s, 1H), 9.61 (s, 1H), 11.33 (s, 1H); Mass: M+H⁺ 373 & 375.

m) The product gave the following data: NMR: 1.05 (t, 3H), 2.4 (q, 2H),3.97 (s, 3H), 3.99 (s, 3H), 7.35 (s, 1H), 7.58 (m, 2H), 8.05 (m, 1H),8.29 (s, 1H), 8.82 (s, 1H), 9.53 (s, 1H), 11.4 (s, 1H); Mass: M+H⁺ 387 &389.

n) The product gave the following data: NMR: 2.08 (s, 3H), 4.0 (s, 6H),7.35 (s, 1H), 7.69 (d, 1H), 7.86 (d, 1H), 8.23 (s, 1H), 8.79 (s, 1H),9.67 (s, 1H), 11.52 (broad s, 1H); Mass: M+H⁺ 391 & 393.

o) The product gave the following data: NMR: 3.40 (s, 3H), 3.98 (s, 3H),4.0 (s, 3H), 4.06 (s, 2H), 7.35 (s, 1H), 7.4 (m, 1H), 7.5 (m, 1H), 8.13(m, 1H), 8.3 (s, 1H), 8.79 (s, 1H), 9.57 (s, 1H), 11.43 (s, 1H); Mass:M+H⁺ 387.

p) The product gave the following data: NMR: 3.44 (s, 3H), 3.99 (s, 3H),4.01 (s, 3H), 4.05 (s, 2H), 7.36 (s, 1H), 7.6 (m, 2H), 8.3 (m, 2H), 8.82(s, 1H), 9.35 (s, 1H), 11.43 (s, 1H); Mass: M+H⁺ 403 & 405.

q) An analogous procedure to that described in Example 3 was used. Theproduct gave the following data: NMR: 4.0 (s, 6H), 7.35 (s, 1H), 7.77(d, 1H), 7.82 (d, 1H), 8.03 (d, 2H), 8.14 (d, 2H), 8.26 (s, 1H), 8.81(s, 1H), 10.52 (s, 1H); Mass: M+H⁺ 478 & 480.

r) The product gave the following data: NMR: 3.99 (s, 3H), 4.01 (s, 3H),7.68 (m, 1H), 7.37 (s, 1H), 7.4 (m, 3H), 7.62 (d, 1H), 7.92 (s, 1H),8.16 (s, 1H), 8.27 (s, 1H), 8.79 (s, 1H), 10.37 (broad s, 1H), 11.35(broad s, 1H); Mass: M+H⁺ 391.

s) The product gave the following data: NMR: 3.99 (s, 3H), 4.01 (s, 3H),7.35 (s, 1H), 7.44 (m, 1H), 7.63 (m, 1H), 7.65 (d, 1H), 8.19 (s, 1H),8.29 (s, 1H), 8.38 (dd, 1H), 8.78 (s, 1H), 8.96 (s, 1H), 10.53 (broad s,1H), 11.37 (broad s, 1H); Mass: M+H⁺ 436 & 438.

t) The product gave the following data: NMR: 2.16 (s, 3H), 3.98 (s, 6H),7.32 (m, 3H), 7.66 (d, 1H), 7.84 (s, 1H), 8.27 (s, 1H), 8.69 (s, 1H),8.78 (s, 1H), 10.91 (broad s, 1H), 11.44 (broad s, 1H); Mass: M+H⁺ 406.

The 4-(5-amino-2-methylanilino)-6,7-dimethoxyquinazoline used as astarting material was prepared as follows:

Using analogous procedures to those described in the portion of Example2 which is concerned with the preparation of starting materials,4-chloro-6,7-dimethoxyquinazoline was reacted with2-methyl-5-nitroaniline to give4-(2-methyl-5-nitroanilino)-6,7-dimethoxyquinazoline hydrochloride;Mass: M+H⁺ 341 and that material was reduced during 5 hours to give4-(5-amino-2-methylanilino)-6,7-dimethoxyquinazoline; Mass: M+H⁺ 311.

Example 244-[2-Methyl-5-(3-dimethylaminobenzamido)anilino]-6,7,8-trimethoxyquinazoline

3-Dimethylaminobenzoyl chloride (105 mg) was added to a suspension of4-(2-methyl-5-aminoanilino)-6,7,8-trimethoxyquinazoline (180 mg) in drymethylene chloride (4 ml) and the resulting mixture was stirred atambient temperature for 18 hours. Methylene chloride (100 ml) was addedand the mixture washed with aqueous sodium hydroxide solution (100 ml),water and brine, dried over sodium sulphate, filtered and evaporatedgive a yellow gum. This was purified by silica column chromatography,eluting with 2% methanol in methylene chloride to yield the titlecompound as a solid (30 mg, 12%); NMR (CDCl₃) 2.22 (s, 3H), 2.97 (s,6H), 3.96 (s, 3H), 4.06 (s, 3H), 4.13 (s, 3H), 6.84 (dd, 1H), 7.05 (m,2H), 2.22 (m, 2H), 7.28 (t, 1H), 7.42 (m, 1H), 7.92 (s, 1H), 7.95 (s,1H), 8.61 (s, 1H); m/s: M+H⁺ 488.

The 3-dimethylaminobenzoyl chloride hydrochloride used as a startingmaterial was prepared as follows:

Oxalyl chloride (0.58 ml) was added to a stirred solution of3-dimethylaminobenzoic acid (1.0 g) in methylene chloride (30 ml)followed by dimethylformamide (30 ml). The reaction was stirred atambient temperature for 1 hour and then evaporated to dryness. There wasthus obtained the required compound as a solid (1.33g, quantitative);NMR: (CDCl₃) 3.25 (s, 6H), 7.75 (t, 1H), 8.27 (d, 1H), 8.39 (m, 2H).

The 4-(5-amino-2-methylanilino)-6,7,8-trimethoxyquinazoline used as astarting material was prepared as follows:

2-Methyl-5-nitroaniline (0.711 g) was added to a suspension of4-chloro-6,7,8-trimethoxyquinazoline hydrochloride (JP 10175972 A2; 1.1g) in isopropanol (40 ml) and the resultant solution heated to 80° C.and stirred for 18 hours. The reaction mixture was evaporated, thenpartitioned between methylene chloride and 2M aqueous sodium hydroxidesolution, the organic phases were washed with water and brine, dried(Na₂SO₄) and evaporated give a yellow solid. This was purified by silicacolumn chromatography, eluting with 2.5% methanol in methylene chlorideThere was thus obtained4-(2-methyl-5-nitroanilino)-6,7,8-trimethoxyquinazoline as a solid (662mg, 45%); NMR: 2.32 (s, 3H), 3.9 (s, 3H), 3.95 (s, 3H), 4.0 (s, 3H),7.59 (d, 1H), 7.66 (s, 1H), (s, 1H), 8.36 (s, 1H), 9.62 (s, 1H); m/s:M+H⁺ 371.

Using similar procedures to those described in the last paragraph of theportion of Example 2 which is concerned with the preparation of startingmaterials, a solution of4-(2-methyl-5-nitroanilino)-6,7,8-trimethoxyquinazoline in a 30:3:1mixture of ethanol, acetic acid and water was reduced at 90° C. during18 hours. Solid sodium carbonate was added after cooling. The filtratewas triturated with diethyl ether and the resultant residue was purifiedby column chromatography eluting with 2.5% methanol in ethyl acetate togive 4-(5-amino-2-methylanilino)-6,7-dimethoxyquinazoline; NMR: (CDCl₃)2.73 (s, 3H), 3.95 (s, 3H), 4.04 (s, 3H), 4.14 (s, 3H), 6.9 (s, 1H),7.21 (m, 2H), 7.64 (s, 1H), 7.96 (d, 1H), 8.50 (s, 1H), 8.72 (s, 1H);Mass: M+H⁺ 341.

Example 254-[4-Fluoro-3-(methoxycarbonylamino)anilino]-6,7-dimethoxyquinazoline

Methyl chloroformate (0.048 ml) was added to a suspension of4-(3-amino-4-fluoroanilino)-6,7-dimethoxyquinazoline (161 mg) andtriethylamine (0.14 ml) in dry methylene chloride (3.5 ml) and theresulting mixture was stirred at ambient temperature for 18 hours.Methylene chloride (100 ml) was added and the mixture washed with waterand brine, dried over magnesium sulphate, filtered and evaporated todryness. The residue was purified by silica column chromatography,eluting with 3% methanol in methylene chloride to yield the titlecompound as a solid (16 mg, 8.4%); NMR: 3.66 (s, 3H), 3.92 (s, 3H), 3.96(s, 3H), 7.16 (s, 1H), 7.22 (t, 1H), 7.57 (m, 1H), 7.82 (s, 1H), 8.01(m, 1H), 8.42 (s, 1H), 9.34 (s, 1H), 9.47 (s, 1H); m/s: M+H⁺ 373.

Example 26 4-[3-(4-Cyanobenzamido)anilino]-6,7-dimethoxyquinazolinehydrochloride

4-Chloro-6,7-dimethoxyquinazoline (225 mg) was added to3-(4-cyanobenzamido)aniline (261 mg) in isopropanol (8 ml). A 1Msolution of hydrogen chloride in diethyl ether (1.0 ml) was added andthe reaction mixture stirred and heated to 85° C. for 18 hours. Aftercooling to room temperature the precipitated solid was isolated andwashed with isohexane and diethyl ether. The title compound was obtainedas a solid (399 mg); NMR: 3.99 (s, 3H), 4.01 (s, 3H), 7.37 (s, 1H), 7.45(m, 2H), 7.65 (m, 1H), 8.02 (m, 2H), 8.12 (m, 2H), 8.20 (m, 1H), 8.31(s, 2H), 8.80 (s, 1H), 10.71 (s, 1H), 11.44 (s, 1H); m/s: M+H⁺ 426.

The 3-(4-cyanobenzamido)aniline used as a starting material was preparedas follows:

4-Cyanobenzoyl chloride (1.0 g) in methylene chloride (20 ml) was addeddiopwise into an ice-cooled solution of m-phenylenediamine (3.24 g) andtriethylamine (0.84 ml) in methylene chloride (100 ml). The reaction wasallowed to stir at ambient temperature for 1 hour. The precipitate wasfiltered and washed with diethyl ether. The title compound was obtainedas a solid (1.0 g, 70%); NMR: 5.00-5.15 (broad s, 2H), 6.31 (m, 1H),6.84 (m, 1H), 6.95 (m, 1H), 7.8 (m, 1H), 7.97 (m, 2H), 8.03 (m, 2H),10.14 (s, 1H); m/s: M+H⁺ 238.

Example 274-(3-Benzamido-4-fluoroanilino)-6-methoxy-7-(3-morpholinopropoxy)quinazoline

4-Pentafluorophenoxy-6-methoxy-7-(3-morpholinopropoxy)quinazoline (242mg) was added to a solution of 3-benzamido-4-fluoroaniline (126 mg) inisopropanol (5 ml). A 1M solution of hydrogen chloride in diethyl ether(1.0 ml) was added and the reaction mixture stirred and heated to 85° C.for 24 hours. After cooling to room temperature the precipitated solidwas isolated and washed with isohexane and diethyl ether. The solid thusobtained was partitioned between 1M aqueous sodium hydroxide solutionand methylene chloride. The organic phase was washed with brine, driedover magnesium sulphate, filtered and evaporated to dryness. The titlecompound was obtained (110 mg, 41%); NMR: 1.94 (m, 2H), 2.37 (m, 4H),2.44 (t, 2H), 3.56 (m, 4H), 3.95 (s, 3H), 4.18 (t, 2H), 7.16 (s, 1H),7.30 (dd, 1H), 7.56 (m, 3H), 7.72 (m, 1H), 7.84 (s, 1H), 8.0 (d, 2H),8.04 (m, 1H), 8.43 (s, 1H), 9.5 (s, 1H), 10.14 (s, 1H); m/s: M+H⁺ 532.

4-(3-Chloropropyl)morpholine used as an intermediate was prepared asfollows:

Morpholine (52.2 ml) and 1-bromo-3-chloropropane (30 ml) were taken upin dry toluene (180 ml) and stirred and heated to 70° C. for 3 hours.The resultant precipitate was filtered off and the filtrate evaporatedto give an orange oil which was purified by vacuum distillationcollecting fractions at 62° C./5 mmHg and 58° C./2 mmHg. The requiredcompound was obtained as an oil (37.9 g, 77%); NMR: 1.85 (m, 2H), 2.3(t, 4H), 2.38 (t, 2H), 3.53 (t, 4H), 3.65 (t, 2H); M/s: M+H⁺ 164.

The 4-pentafluorophenoxy-6-methoxy-7-(3-morpholinopropoxy)quinazolineused as a starting material was prepared as follows:

A mixture of 2-amino-4-benzyloxy-5-methoxybenzamide (J. Med. Chem. 1977,vol 20, 146-149, 10 g) and Gold's reagent (7.4 g) in dioxane (100 ml)was stirred and heated at reflux for 24 hours. Sodium acetate (3.02 g)and acetic acid (1.65 ml) were added to the reaction mixture and it washeated for a further 3 hours. The mixture was evaporated to dryness,water was added to the residue and the solid was filtered off, washedwith water and dried. Recrystallization from acetic acid gave7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one (8.7 g, 84%).

7-Benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one (10.1 g) was suspendedin thionyl chloride (200 ml) then dimethylformamide (0.5 ml) added andthe resultant mixture heated to 80° C. and stirred for 3 hours. Thereaction mixture was evaporated and azeotroped with toluene to yield4-chloro-7-hydroxy-6-methoxyquinazoline as a solid (12.1 g, 100%); NMR:4.88 (s, 3H), 5.25 (s, 2H), 7.44 (s, 1H), 7.49 (s, 1H), 7.32-7.52 (m,5H), 8.83 (s, 1H); m/s: M+H⁺ 283.

Potassium carbonate (17.2 g) was added to a suspension of4-chloro-7-hydroxy-6-methoxyquinazoline (12.0 g) and2,3,4,5,6-pentafluorophenol (7.88 g) in dimethylformamide (150 ml). Theresultant mixture was stirred and heated to 100° C. for 18 hours. Themixture was evaporated and the residue partitioned between water andethyl acetate, the organic phase was washed with brine, dried overmagnesium sulphate, filtered and evaporated to dryness to yield7-benzyloxy-6-methoxy-4-pentafluorophenoxyquinazoline as a solid (14.6g, 89%); NMR (CDCl₃) 4.08 (s, 3H), 5.35 (s, 2H), 7.4 (s, 1H), 7.52 (s,1H), 7.32-7.52 (m, 5H), 8.56 (s, 1H); m/s: M+H⁺ 449.

A solution of 7-benzyloxy-6-methoxy-4-pentafluorophenoxyquinazoline(14.6 g) in trifluoroacetic acid (100 ml) was heated to 70° C. andstirred for 1 hour. The mixture was evaporated to dryness taken up insaturated aqueous sodium bicarbonate solution and stirred for 30minutes. It was then filtered, washed with water and dried under vacuumat 40° C. overnight to yield7-hydroxy-6-methoxy-4-pentafluorophenoxyquinazoline as a solid (11.6 g,99%); NMR: 3.99 (s, 3H), 7.28 (s, 1H), 7.56 (s, 1H), 8.52 (s, 1H) 11.0(s, 1H); m/s: M+H⁺ 359.

Potassium carbonate (12.5 g) was added to a suspension of7-hydroxy-6-methoxy-4-pentafluorophenoxyquinazoline (7.73 g) and4-(3-chloropropyl)morpholine (4.28 g) in dimethylformamide (180 ml). Theresultant mixture was stirred and heated to 100° C. for 4 hours. Aftercooling to room temperature, the inorganic solids were filtered off andthe filtrate was evaporated and the residue was partitioned betweenwater and ethyl acetate, the organic phases were washed with brine,dried over magnesium sulphate, filtered and evaporated to dryness toyield 4-pentafluorophenoxy-6-methoxy-7-(3-morpholinopropoxy)quinazolineas a solid (9.37 g, 89%); NMR: 1.98 (m, 2H), 2.38 (m, 4H), 2.42 (t, 2H),3.55 (t, 4H), 3.99 (s, 3H), 4.28 (t, 2H), 7.45 (s, 1H), 7.56 (s, 1H),8.6 (s, 1H); m/s: M+H 486.

The 3-benzamido-4-fluoroaniline (alternatively named asN-(5-amino-2-fluorophenyl)benzamide) used as a starting material wasprepared as follows:

Triethylamine (5.85 ml) was added to a an ice-cooled solution of2-fluoro-5-nitroaniline (3.9 g) in dry methylene chloride under an argonatmosphere. Benzoyl chloride (4.18 ml) was added gradually. Theresulting mixture was stirred at ambient temperature for 18 hours. Thereaction mixture was partitioned between water and methylene chloride,the organic phase was washed with saturated aqueous sodium bicarbonatesolution and brine, dried over magnesium sulphate, filtered andevaporated to dryness to give a sticky solid. Trituration with hotisohexane and diethyl ether gave N-(2-fluoro-5-nitrophenyl)benzamide asa solid (3.2 g, 49%); NMR (CDCl₃) 7.26 (dd, 1H), 7.6 (m, 3H), 7.91 (d,2H), 8.03 (m, 1H), 8.15 (broad s, 1H), 9.48 (dd, 1H); m/s: M+H⁺ 261.

N-(2-Fluoro-5-nitrophenyl)benzamide (3.2 g) was dissolved in methanol(250 ml) under an argon atmosphere. 10% palladium on activated carbon(250 mg) was added and the argon atmosphere replaced with hydrogen. Thereaction mixture was stirred at ambient temperature until the requisitevolume of hydrogen gas was taken up. The catalyst was removed byfiltration and the filtrate evaporated to give the required compound aswhite solid (2.66 g, 94%); NMR: (CDCl₃) 3.64 (broad s, 2H), 6.36 (m,1H), 6.92 (dd, 1H), 7.53 (m, 3H), 7.87 (d, 2H), 7.93 (dd, 1H), 8.01(broad s, 1H); m/s: M+H⁺ 231.

Examples 28-45

Using an analogous procedure to that described in Example 26 or 27, theappropriate 4-chloro or 4-pentafluorophenoxyquinazoline was reacted withthe appropriate aniline to give the compounds described in the followingtable. Unless otherwise stated, each compound prepared by the method ofExample 26 were obtained as the hydrochloride salt. In the preparationof each compound by the method of Example 27, the step of treatment with1M aqueous sodium hydroxide was omitted and each such product wasobtained as a dihydrochloride salt.

Ex. No. R¹ R² R³ R⁴ Method Note 28 Me H H 3-dimethylaminophenyl Ex. 26a) 29 Me Me H phenyl Ex. 26 b) 30 Me Cl H phenyl Ex. 26 c) 31 Me Me H4-cyanophenyl Ex. 26 d) 32 Me Cl H 4-cyanophenyl Ex. 26 e) 33 Me Me H3-dimethylaminophenyl Ex. 26 f) 34 Me Cl H 3-dimethylaminophenyl Ex. 26g) 35 Me Me H 3,4-dimethoxyphenyl Ex. 26 h) 36 Me F F phenyl Ex. 26 i)37 Me Cl F 3-dimethylaminophenyl Ex. 26 j) 38 3-morpholinopropyl Me H3-dimethylaminophenyl Ex. 26 k) 39 Me Cl F methoxymethyl Ex. 26 l) 403-pyrid-3-ylpropyl H F methoxymethyl Ex. 27 m) 41 3-morpholinopropyl H Fmethoxymethyl Ex. 27 n) 42 2-morpholinoethyl H F methoxymethyl Ex. 27 o)43 2-pyrrolidin-1-ylethyl H F methoxymethyl Ex. 27 p) 44 Me Me H3-morpholinophenyl Ex. 26 q) 45 Me Me H 2-morpholinopyrid-4-yl Ex. 26 r)Notes a) The product gave the following data: NMR: 3.0(s, 6H), 3.98(s,3H), 4.0(s, 3H), 7.2-7.6(broad m, 7H), 7.69(m, 2H), 8.2(m, 1H), 8.38(s,1H), 8.8(s, 1H), 10.5(s, 1H), 11.55(s, 1H); Mass: M+H⁺ 444.

The N-(3-aminophenyl)-3-dimethylaminobenzamide used as a startingmaterial was prepared as follows:

3-Nitroaniline (3.84 g) in methylene chloride (50 ml) was added dropwiseto an ice-cooled solution of 3-dimethylaminobenzoyl chloride (9.74 gcrude weight) and 4-dimethylaminopyridine (308 mg) in methylene chloride(30 ml) and triethylamine (8.8 ml). The reaction was stirred at ambienttemperature for 72 hours and then partitioned between methylene chlorideand saturated sodium bicarbonate. The organic phase was then washed withbrine, dried over magnesium sulphate, filtered and evaporated to drynessaffording N-(3-nitrophenyl)-3-dimethylaminobenzamide as a solid (8.64 g,99.9%); NMR (CDCl₃) 3.02 (s, 6H), 6.9 (m, 1H), 7.09 (s, 1H), 7.25 (m,1H), 7.35 (t, 1H), 7.53 (t, 1H), 7.99 (m, 1H), 8.05 (broad s, 1H), 8.1(m, 1H), 8.5 (m, 1H); m/s: M+H⁺ 286.

10% Palladium on carbon (637 mg) was added to a stirred solution ofN-(3-nitrophenyl)-3-dimethylaminobenzamide (6.37 g) in methanol (180 ml)under an argon atmosphere. Ammonium formate (14.0 g) was added and thereaction heated to 70° C. for 1 hour. After cooling the reaction wasfiltered through diatomaceous earth (Celite®). The filtrate wasconcentrated under vacuum until crystallisation began, water was addedand with scratching a solid was achieved. The solid was collected anddried in a vacuum oven for 18 hours to yield the required compound (5.02g, 88%); NMR (CDCl₃) 3.0 (s, 6H), 6.47 (m, 1H), 6.8 (s, 1H), 6.87 (m,1H), 7.06 (m, 1H), 7.11 (m, 1H), 7.3 (m, 3H), 7.75 (broad s, 1H); m/s:M+H⁺ 256.

b) The product gave the following data: NMR: 2.14 (s, 3H), 3.99 (s, 3H),4.0 (s, 3H), 7.34 (m, 2H), 7.50 (broad m, 3H), 7.64 (m, 1H), 7.92 (m,3H), 8.33 (s, 1H), 8.71 (s, 1H), 10.37 (s, 1H), 11.53 (s, 1H); Mass:M+H⁺ 415.

The N-(3-amino-4-methylphenyl)benzamide used as a starting material wasprepared as follows:

Benzoyl chloride (1.9 ml) was added to a stirred mixture of2,4-diaminotoluene (2 g), triethylamine (5.57 ml) and methylene chloride(80 ml) and the mixture was stirred at ambient temperature for 16 hours.The mixture was washed with a saturated aqueous solution of sodiumbicarbonate. The organic phase was dried over magnesium sulphate,filtered and evaporated to dryness. The residue was triturated with amixture of ethyl acetate and diethyl ether to yield the requiredcompound (1.32 g); NMR: 2.01 (s, 3H), 4.8 (s, 2H), 6.82 (m 2H), 7.11 (s,1H), 7.5 (m, 3H), 7.91 (m, 2H), 9.86 (s, 1H); m/s M+H⁺ 227.

c) The product was purified by column chromatography eluting with 10%methanol in methylene chloride. The resultant product gave the followingdata: NMR: 4.0 (2s, 6H), 7.4 (s, 1H), 7.50-7.65 (broad m, 4H), 7.81 (m,1H), 7.98 (m, 2H), 8.13 (m, 1H), 8.32 (s, 1H), 8.79 (s, 1H), 10.60 (s,1H), 11.73 (s, 1H); Mass: M+H⁺ 435 & 437.

The N-(3-amino-4-chlorophenyl)benzamide used as a starting material wasprepared as follows:

Benzoyl chloride (5.2 ml) was added to a stirred mixture of2,4-diaminochlorobenzene (6.42 g), triethylamine (12.5 ml) and methylenechloride (100 ml) which had been cooled to 0° C. The mixture was allowedto warm to ambient temperature and was stirred for 16 hours. The mixturewas evaporated and the residue was triturated under a saturated aqueoussodium bicarbonate solution. The resultant solid was isolated, washed inturn with water and isohexane and dried under vacuum at 55° C. to yieldthe required compound (10.38 g); NMR 5.32 (s, 2H), 6.9 (m, 1H), 7.1 (d,1H), 7.37 (d, 1H), 7.52 (m, 3H), 7.9 (d, 2H), 10.05 (s, 1H).

d) The product gave the following data: NMR: 2.14 (s, 3H), 3.91 (2s,6H), 7.15 (s, 1H), 7.29 (d, 1H), 7.59 (m, 1H), 7.81 (m, 2H), 8.00 (m,2H), 8.09 (m, 2H), 8.28 (s, 1H), 9.39 (s, 1H), 10.46 (s, 1H); Mass: M+H⁺440.

The N-(3-amino-4-methylphenyl)-4-cyanobenzamide used as a startingmaterial was prepared as follows:

Triethylamine (23 ml) was added to a suspension of3-nitro-4-methylaniline (0.8 g), 4-cyanobenzoyl chloride (13.1 g),4-dimethylaminopyridine (0.8 g) in methylene chloride (200 ml) which hadbeen cooled to 0° C. The reaction mixture was allowed to warm to ambienttemperature and was stirred for 5 hours. The mixture was partitionedbetween methylene chloride and 0.5M hydrochloric acid solution. Theorganic phase was dried over magnesium sulphate, filtered and evaporatedto dryness. The residue was triturated under isohexane and the resultingsolid was isolated and dried under vacuum at 55° C. to yieldN-(4-methyl-3-nitrophenyl)-4-cyanobenzamide (18.3 g); NMR: 2.5 (s, 3H),7.49 (d, 1H), 7.96 (m, 1H), 8.05 (d, 2H), 8.12 (d, 2H), 8.51 (d, 1H),10.77 (s, 1H).

A solution of tin(II) chloride dihydrate (15.4 g) in concentratedhydrochloric acid (80 ml) was added to a suspension ofN-(4-methyl-3-nitrophenyl)-4-cyanobenzamide (6.39 g) in acetic acid (120ml). The mixture was stirred and heated to reflux for 2 hours. Themixture was allowed to cool to ambient temperature and was basified bythe addition of 2M sodium hydroxide solution. The precipitated solid wasisolated and dried under vacuum at 55° C. to yield the required compound(5.62 g); NMR: 2.01 (s, 3H), 4.85 (s, 2H), 6.8 (d, 1H), 6.86 (d, 1H),7.11 (s, 1H), 7.96 (d, 2H), 8.06 (d, 2H), 10.11 (s, 1H).

e) The product gave the following data: NMR: 3.99 (2s, 6H), 7.41 (s,1H), 7.62 (m, 1H), 7.82 (m, 1H), 7.95-8.15 (m, 6H), 8.35 (s, 1H), 8.32(s, 1H), 8.88 (s, 1H), 10.9 (s, 1H), 11.82 (s, 1H); Mass: M+H⁺ 460 &462.

The N-(3-amino-4-chlorophenyl)-4-cyanobenzamide used as a startingmaterial was prepared as follows:

4-Cyanobenzoyl chloride (11.92 g) was added slowly to a stirred solutionof 4-chloro-3-nitroaniline (10.4 g) in pyridine (20 ml) and the mixturewas stirred and heated to 115° C. for 18 hours. The mixture was cooledto ambient temperature and poured into water (150 ml) and stirred for 30minutes. The resultant precipitate was isolated, washed with water anddried to yield N-[4-chloro-3-nitrophenyl]-4-cyanobenzamide (18 g); m.p.213° C.; NMR: 7.78 (d, 1H), 8.05 (m, 3H), 8.1 (d, 2H), 8.58 (s, 1H),10.93 (s, 1H).

N-[4-chloro-3-nitrophenyl]4-cyanobenzamide (3.6 g) was added to astirred suspension of iron powder (10 g) in a mixture of ethanol (130ml), water (30 ml) and glacial acetic acid (4 ml). The mixture washeated to 75° C. for 1 hour and thereafter, whilst hot, basified by theaddition of sodium carbonate. The mixture was filtered and the filtratewas evaporated. The resultant solid was stirred in water for 3 hours.The solid was isolated and dried to yield the required compound (2.7 g);m.p. 237.7° C.; NMR: 5.44 (s, 2H), 6.98 (m, 1H), 7.21 (d, 1H), 7.42 (d,1H), 8.07 (d, 2H), 8.14 (d, 2H), 10.36 (s, 1H).

f) No hydrochloric acid or hydrogen chloride in diethyl ether was used.The product gave the following data: NMR: 2.15 (s, 3H), 2.93 (s, 6H),3.99 (2s, 6H), 6.91 (m, 1H), 7.21 (m, 2H), 7.3 (m, 3H), 7.66 (m, 1H),7.88 (m, 1H), 8.26 (s, 1H), 8.71 (s, 1H), 10.23 (s, 1H), 11.38 (s, 1H);Mass: M+H⁺ 475.

The N-(3-amino-4-methylphenyl)-3-dimethylaminobenzamide used as astarting material was prepared as follows:

Oxalyl chloride (13.0 ml) was added dropwise to a stirred mixture of3-dimethylaminobenzoic acid (20.3 g) and N,N-dimethylformamide (a fewdrops) which had been cooled to 0° C. The mixture was allowed to warm toambient temperature and was stirred for 4 hours. The resultant mixturewas evaporated and the residue was dissolved in methylene chloride (150ml). 4-Methyl-3-nitroaniline (15.2 g) and triethylamine (27.9 ml) wereadded in turn and the resultant mixture was stirred at ambienttemperature for 16 hours. The reaction mixture was washed in turn withwater, with a saturated solution of sodium bicarbonate and with brine,dried over magnesium sulphate, filtered and evaporated to dryness. Theresidue was triturated under a mixture of ethyl acetate and isohexane.The solid so obtained was filtered off and recrystallized from ethanolto yield N-(4-methyl-3-nitrophenyl)-3-dimethylaminobenzamide (6.1 g);NMR: 2.46 (s, 3H), 2.95 (s, 6H), 6.92 (d, 1H), 7.22 (m, 2H), 7.32 (t,1H), 7.45 (d, 1H), 7.97 (d, 1H), 8.53 (s, 1H), 10.43 (s, 1H); m/z M+H⁺300.

N-(4-methyl-3-nitrophenyl)-3-dimethylaminobenzamide (8.25 g) was addedto a stirred suspension of ammonium formate (17.4 g), and 10%palladium-on-carbon (1 g) in methanol (250 ml). The mixture was stirredand heated to reflux for 4 hours. The mixture was allowed to cool andthen filtered. The filtrate was evaporated and water was added to theresidue. The resultant solid was isolated and washed in turn with water,with ethyl acetate and with diethyl ether. The solid was dried in avacuum oven at 40° C. to yield the required compound (6.89 g); NMR: 2.0(s, 3H), 2.94 (s, 6H), 4.78 (s, 2H), 6.82 (m, 3H), 7.07 (s, 1H), 7.17(m, 2H), 7.25 (m, 1H), 9.74 (s, 1H); m/z M+H⁺ 270.

g) The product gave the following data: NMR: 3.02 (s, 6H), 3.99 (2s,6H), 7.25-7.75 (broad m, 7H), 7.88 (m, 1H), 8.11 (m, 1H), 8.37 (s, 1H),8.78 (s, 1H), 10.7 (s, 1H), 11.84 (s, 1H); Mass: M+H⁺ 478 & 480.

The N-(3-amino-4-chlorophenyl)-3-dimethylaminobenzamide used as astarting material was prepared as follows:

A solution of 3-dimethylaminobenzoyl chloride hydrochloride (20 g) inmethylene chloride (100 ml) was added dropwise over 2 hours to asolution of 4-chloro-3-aminoaniline (14.25 g) and triethylamine (38 ml)in methylene chloride (500 ml), and the reaction stirred at ambienttemperature for 18 hours. The precipitated solid was collected to givethe title compound (29.7 g, quantitative): NMR: 2.94 (s, 3H), 5.28 (s,2H), 6.88 (m, 2H), 7.09 (d, 1H), 7.16 (m, 2H), 7.28 (dd, 1H), 7.33 (m,1H), 9.91 (s, 1H); m/s 290, 292.

h) Hydrochloric acid (0.1 ml) was used instead of hydrogen chloride indiethyl ether (1.0 ml). Filtered solid was impure and so was purified bycolumn chromatography eluting with 5% methanol in methylene chloride.The product gave the following data: NMR: 3.83 (2s, 6H), 3.96 (2s, 6H),7.24 (m, 1H), 7.3 (m, 2H), 7.54 (m, 1H), 7.61 (m, 2H), 7.81 (m, 1H),8.02 (s, 1H), 8.49 (s, 1H), 9.88 (s, 1H); Mass: M+H⁺ 475.

The N-(3-amino-4-methylphenyl)-3,4-dimethoxybenzamide used as a startingmaterial was prepared as follows:

A solution of 3,4-dimethoxybenzoyl chloride (13.2 g) in methylenechloride (200 ml) was added dropwise to a stirred mixture of4-methyl-3-nitroaniline (10 g), pyridine (21.3 ml),4-dimethylaminopyridine (0.4 g) and methylene chloride (100 ml) and theresultant solution was stirred at ambient temperature for 18 hours. Thereaction mixture was washed with 2M hydrochloric acid and water. driedover magnesium sulphate, filtered and evaporated to dryness. The residuewas triturated under diethyl ether and the resultant solid was driedunder vacuum at 60° C. There was thus obtainedN-(4-methyl-3-nitrophenyl)-3,4-dimethoxybenzamide (18.1 g); m.p.148-149° C.; NMR: (CDCl₃) 2.58 (s, 3H), 3.96 (s, 6H), 6.92 (d, 1H), 7.33(d, 1H), 7.43 (m, 1H), 7.51 (d, 1H), 7.9 (m, 1H), 7.97 (broad s, 1H),8.24 (d, 1H).

Ammonium formate (33.9 g) was added to a stirred suspension ofN-(4-methyl-3-nitrophenyl)-3,4-dimethoxybenzamide (17 g) and 10%palladium-on-carbon (4 g) in ethanol (650 ml) and the mixture wasstirred and heated to reflux for 1.5 hours. The reaction mixture wasallowed to cool to ambient temperature and filtered. The filtrate wasevaporated and the residue was partitioned between methylene chlorideand a saturated aqueous sodium bicarbonate solution. The organic phasewas washed with water, dried over magnesium sulphate, filtered andevaporated to dryness. The residue was triturated under diethyl etherand the resultant solid was dried under vacuum at 60° C. to yield therequired compound (12.6 g); m.p. 143-144° C.; NMR: (CDCl₃) 2.13 (s, 3H),3.65 (broad s, 2H), 3.93 (s, 6H), 6.73 (m, 1H), 6.93 (d, 1H), 6.87 (m,1H), 7.0 (m, 1H), 7.28 (d, 1H), 7.36 (m, 1H), 7.48 (d, 1H), 7.7 (broads, 1H).

i) The product gave the following data: NMR: 4.0 (s, 6H), 7.37 (s, 1H),7.56 (m, 4H), 7.79 (dd, 1H), 7.97 (d, 2H), 8.27 (s, 1H), 8.82 (s, 1H),10.29 (broad s, 1H), 11.58 (broad s, 1H); Mass: M+H+ 437.

The N-(5-amino-2,4-difluorophenyl)benzamide used as a starting materialwas prepared as follows:

1,5-Difluoro-2,4-dinitrobenzene (2.48 g) was dissolved in absoluteethanol (150 ml) under an argon atmosphere. 10% palladium on activatedcarbon (250 mg) was added and the argon atmosphere replaced withhydrogen. The reaction mixture was stirred at ambient temperature untilthe requisite volume of hydrogen gas was taken up. The catalyst wasremoved by filtration and the filtrate evaporated to give a black solid.This was dissolved in dry methylene chloride (150 ml) and the solutionfiltered to remove insoluble material. Triethylamine (1.86 ml) was addedfollowed by benzoyl chloride (0.9 ml) and the resulting mixture wasstirred at ambient temperature for 18 hours. The reaction mixture waspartitioned between water and methylene chloride, the organic phase waswashed with saturated aqueous sodium bicarbonate solution and brine,dried over magnesium sulphate, filtered and evaporated to dryness togive a brown oil. This was purified by eluting through a silica columnwith 60:40 diethyl ether/isohexane yielding the required compound as asolid (1.06 g, 35%); NMR (CDCl₃) 3.67 (broad s, 2H), 6.85 (dd, 1H), 7.54(m, 3H), 7.88 (d, 2H), 8.01 (dd, 1H); m/s: M+H⁺ 249.

j) The product was purified by column chromatography, eluting with97:2:1 methylene chloride/methanol/aqueous ammonia solution. Theresultant product gave the following data: NMR: 3.02 (s, 6H), 4.05 (s,6H), 6.92 (m, 1H), 7.12 (m, 2H), 7.32 (m, 2H), 7.56 (s, 1H), 8.05 (s,1H), 8.73 (s, 1H), 9.58 (d, 1H); Mass: M+H⁺ 496 & 498.

The N-(5-amino-4-chloro-2-fluorophenyl)-3-dimethylaminobenzamide used asa starting material was prepared as follows:

Pyridine (2.0 ml) was added to a suspension ofN-(5-amino-2-chloro-4-fluorophenyl)phthalimide (2.9 g) and3-dimethylaminobenzoyl chloride hydrochloride (3.06 g) in methylenechloride under an argon atmosphere. The resultant mixture was stirred atambient temperature for 18 hours. The reaction mixture was diluted withmethylene chloride (200 ml) and washed with saturated aqueous coppersulphate solution, water and brine, then dried over magnesium sulphate,filtered and evaporated to dryness. The residue was triturated with warmethyl acetate, filtered and washed with ethyl acetate and diethyl etherto giveN-(5-amino-4-chloro-2-fluorophenyl)phthalimide-3-dimethylaminobenzamideas a solid (2.46 g, 56%); NMR: 2.94 (s, 6H), 6.94 (m, 1H), 7.28 (m, 3H),7.80-7.92 (m, 1H), 7.94 (m, 2H), 8.02 (m, 2H); m/s: M+H⁺ 438, 440.

Ethanolamine (0.68 ml) was added to a solution ofN-(5-amino-4-chloro-2-fluorophenyl)phthalimide-3-dimethylaminobenzamide(2.4 g) in dry methylene chloride (40 ml). The reaction mixture wasstirred at ambient temperature for 4 hours. The mixture was diluted withmethylene chloride (200 ml) and the resulting solution washed with waterand brine, dried over sodium sulphate, filtered and evaporated todryness to yield the required compound as a solid (1.26 g, 73%); NMR(CDCl₃) 3.02 (s, 6H), 3.94 (s, 2H), 4.0 (broad s, 2H), 6.88 (m, 1H),7.04 (m, 1H), 7.07 (s, 1H), 7.25 (m, 1H), 7.32 (t, 1H), 7.98 (broad s,8.08 (d, 1H); m/s: M+H⁺ 308, 310.

k) The free base was generated by partitioning between methylenechloride and saturated sodium bicarbonate, the organic phase was thendried with brine and sodium sulphate, filtered and the filtrate wasevaporated to yield a solid. The product gave the following data: NMR:1.93 (m, 2H), 2.12 (s, 3H), 2.4 (m, 6H), 2.94 (s, 6H), 3.56 (m, 4H),3.93 (s, 3H), 4.16 (m, 2H), 6.9 (m, 1H), 7.05-7.35 (broad m, 5H), 8.6(m, 1H), 7.77 (m, 1H), 7.82 (s, 1H), 8.27 (s, 1H), 8.27 (s, 1H), 9.35(s, 1H), 10.08 (s, 1H); Mass: M+H⁺ 570.

l) The product gave the following data: NMR: 3.36 (s, 3H), 3.98 (s, 6H),4.05 (s, 2H), 7.37 (s, 1H), 7.76 (d, 1H), 8.04 (d, 1H), 8.23 (s, 1H),8.77 (s, 1H), 9.73 (s, 1H), 11.57 (s, 1H); Mass: M+H⁺ 421 & 423.

The N-(5-amino-4-chloro-2-fluorophenyl)-2-methoxyacetamide used as astarting material was prepared as follows:

Methoxyacetyl chloride (0.65 ml) was added dropwise to a solution ofN-(2-chloro-4-fluoro-5-aminophenyl)phthalimide (1.39 g) andtriethylamine (1.16 ml) in dry methylene chloride (45 ml) and theresulting mixture was stirred at ambient temperature for 2 hours. Thereaction mixture was diluted with methylene chloride and washed withsaturated aqueous sodium bicarbonate solution and brine, dried oversodium sulphate, filtered and evaporated to dryness to yieldN-[2-chloro-4-fluoro-5-(2-methoxyacetamido)phenyl]phthalimide as a solid(1.72 g, 99%); NMR (CDCl₃): 3.53 (s, 3H), 4.04 (s, 2H), 7.37 (d, 1H),7.81 (m, 2H), 7.98 (m, 2H), 8.57 (d, 1H), 8.62 (broads s, 1H); m/s:[M−H]⁻ 361, 363.

Ethanolamine (0.6 ml) was added to a solution ofN-[2-chloro-4-fluoro-5-(2-methoxyacetamido)phenyl]phthalimide (1.408 g)in dry methylene chloride. The reaction mixture was stirred at ambienttemperature for 4 hours. The mixture was diluted with methylene chloride(200 ml) and the resulting solution washed with water and brine, driedover sodium sulphate, filtered and evaporated to dryness to yield therequired product as a solid (quantitative); NMR (CDCl₃) 3.5 (s, 3H),3.96 (broad s, 2H), 4.02 (s, 2H), 7.03 (d, 1H), 7.91 (d, 1H), 8.45(broad s, 1H); m/s: M+H⁺ 233, 235.

m) Prepared using two equivalents of 1M hydrogen chloride solution indiethyl ether. The product was obtained as the dihydrochloride salt andgave the following data: NMR: 2.24 (m, 2H), 3.0 (t, 2H), 3.38 (s, 3H),3.97 (s, 3H), 4.05 (s, 2H), 4.24 (t, 2H), 7.37 (t, 1H), 7.42 (s, 1H),7.92 (dd, 1H), 8.13 (dd, 1H), 8.38 (s, 1H), 8.44 (d, 1H), 8.76 (d, 1H),8.79 (s, 1H), 9.6 (s, 1H), 11.57 (s, 1H); Mass: M+H⁺ 492.5.

The 6-methoxy-4-pentafluorophenoxy-7-(3-pyrid-3-ylpropoxy)quinazolineused as a starting material was prepared as follows:

Under an argon atmosphere, diethyl azodicarboxylate (4.9 ml) was addeddropwise to an ice cooled suspension of7-hydroxy-6-methoxy-4-pentafluorophenoxyquinazoline (7.98 g),3-(3-pyridyl)-1-propanol (3.16 ml) and triphenylphosphine (8.8 g) in drymethylene chloride (200 ml). The resultant mixture was stirred atambient temperature for 2 hours. The reaction mixture was evaporated andthe residue purified by trituration with diethyl ether followed byelution through a silica column with 5% methanol in methylene chlorideyielding the required compound as a solid (4.96 g, 47%); NMR (CDCl₃) 2.3(m, 2H), 2.92 (t, 2H), 4.07 (s, 3H), 4.23 (t, 2H), 7.24 (m, 1H), 7.32(s, 1H), 7.52 (s, H), 7.56 (m, 1H), 8.47 (d, 1H), 8.52 (s, 1H), 8.58 (s,1H); m/s: M+H⁺ 472.

The N-(5-amino-2-fluorophenyl)-2-methoxyacetamide used as a startingmaterial was prepared as follows:

A solution of methoxyacetyl chloride (5.85 ml) in methylene chloride (50ml) was added dropwise to a solution of 2-fluoro-5-nitroaniline (5.06 g)and triethylamine (8.92 ml) in methylene chloride (150 ml) under anargon atmosphere. The resultant mixture was stirred at ambienttemperature for 5 hours, then poured into water and extracted withmethylene chloride. The organic phases were washed with brine, driedover magnesium sulphate, filtered and evaporated to dryness to yieldN-(2-fluoro-5-nitrophenyl)-2-methoxyacetamide as a solid (7.7 g, 100%);NMR: 3.26 (s, 2H), 4.5 (s, 3H), 7.57 (t, 1H), 8.03 (m, 1H), 8.82 (m,1H), 9.83 (s, 1H); m/s: M+H⁺ 229.

Iron powder (9.05 g) was added to a solution ofN-(2-fluoro-5-nitrophenyl)-2-methoxyacetamide (7.69 g) in a mixture ofethanol (320 ml) and glacial acetic acid (3.2 ml) under an argonatmosphere. The resultant mixture was heated to 90° C. and stirred for 4hours. Sodium carbonate was added and the mixture stirred for 10minutes, then filtered warm through diatomaceous earth (Celite®) andwashed with warm ethanol and methylene chloride. The filtrate wasevaporated, the residue taken up in water and the resulting solidfiltered off, washed with water and diethyl ether. The filtrate waspartitioned between ethyl acetate and water, the organic liquors werewashed with brine, dried over sodium sulphate, filtered and evaporatedto dryness to yield the required compound as a solid (5.38 g, 84%); NMR:(CDCl₃) 3.52 (s, 3H), 4.03 (s, 2H), 6.33 (m, 1H), 6.88 (t, 1H), 8.82 (m1H), 9.83 (s, 1H); m/z M+H⁺ 229.

n) Prepared using two equivalents of 1M hydrogen chloride solution indiethyl ether. The product was obtained as the dihydrochloride salt andgave the following data: NMR: 2.32 (m, 2H), 3.1 (m, 2H), 3.22-3.53 (m,4H), 3.38 (s, 3H), 3.8-4.0 (m, 4H), 4.0 (s, 3H), 4.06 (s, 2H), 4.28 (t,2H), 7.37 (t, 1H), 7.41 (s, 1H), 7.51 (m, 1H), 8.13 (dd, 1H), 8.37 (s,1H), 8.79 (s, 1H), 9.59 (s, 1H), 11.47 (s, 1H); Mass: M+H⁺ 500.

o) Prepared using two equivalents of 1M hydrogen chloride solution indiethyl ether. The product was obtained as the dihydrochloride salt andgave the following data: NMR: 3.25-3.45 (m, 4H), 3.38 (s, 3H), 3.66 (t,2H), 3.95 (m, 4H), 4.02 (s, 3H), 4.08 (s, 2H), 4.68 (t, 2H), 7.38 (t,1H), 7.44 (s, 1H), 7.52 (m, 1H), 8.13 (dd, 1H), 8.45 (s, 1H), 8.8 (s,1H), 9.6 (s, 1H), 11.64 (s, 1H); Mass: M+H⁺ 486.5.

The 6-methoxy-7-(2-morpholinoethoxy)-4-pentafluorophenoxyquinazolineused as a starting material was prepared by the reaction of2-morpholinoethanol and7-hydroxy-6-methoxy-4-pentafluorophenoxyquinazoline using an analogousprocedure to that described in Note m) above for the preparation of6-methoxy-4-pentafluorophenoxy-7-(3-pyrid-3-ylpropoxy)quinazoline. Therequired material gave the following data: NMR: 2.5 (m, 4H), 2.78 (t,2H), 3.58 (t, 4H), 3.97 (s, 3H), 4.32 (t, 2H), 7.48 (s, 1H), 7.56 (s,1H), 8.6 (s, 1H); Mass: M+H⁺ 472.

p) Prepared using two equivalents of 1M hydrogen chloride solution indiethyl ether. The product was obtained as the dihydrochloride salt andgave the following data: NMR: 1.85 (m, 2H), 2.02 (m, 2H), 3.12 (m, 2H),3.38 (s, 3H), 3.61 (m, 2H), 3.72 (m, 2H), 4.03 (s, 3H), 4.08 (s, 2H),4.6 (t, 2H), 7.38 (t, 1H), 7.42 (s, 1H), 7.52 (m, 1H), 8.15 (dd, 1H),8.42 (s, 1H), 8.79 (s, 1H), 9.59 (s, 1H), 11.53 (s, 1H); Mass: M+H⁺470.5.

The6-methoxy-7-(2-pyrrolidin-1-ylethoxy)-4-pentafluorophenoxyquinazolineused as a starting material was prepared by the reaction of2-pyrrolidin-1-ylethanol and7-hydroxy-6-methoxy-4-pentafluorophenoxyquinazoline using an analogousprocedure to that described in Note m) above for the preparation of6-methoxy-4-pentafluorophenoxy-7-(3-pyrid-3-ylpropoxy)quinazoline. Therequired material gave the following data: NMR: 1.65 (m, 4H), 2.56 (m,4H), 2.88 (t, 2H), 3.99 (s, 3H), 4.3 (t, 2H), 7.45 (s, 1H), 8.6 (s, 1H);Mass: M+H⁺ 456.

q) The product was obtained as the dihydrochloride salt and gave thefollowing data: NMR: 2.16 (s, 3H), 3.17 (m, 4H), 3.73 (m, 4H), 4.0 (s,3H), 4.01 (s, 3H), 7.17 (d, 1H), 7.37 (m, 4H), 7.46 (s, 1H), 7.66 (d,1H), 7.87 (s, 1H), 8.33 (s, 1H), 8.72 (s, 1H), 10.29 (broad s, 1H),11.52 (broad s, 1H); Mass: M+H⁺ 500.

The N-(3-amino-4-methylphenyl)-3-morpholinobenzamide used as a startingmaterial was prepared as follows:

A mixture of ethyl 3-bromobenzoate (1.92 ml), morpholine (1.25 ml),2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.336 g), sodiumtert-butoxide (1.615 g) and tris(dibenzylideneacetone)dipalladium(0)(0.33 g) and toluene (25 ml) was stirred and heated to 90° C. for 18hours under argon. The reaction mixture was allowed to cool to ambienttemperature and extracted with 1M hydrochloric acid. The aqueous phasewas basified with concentrated sodium hydroxide solution and extractedwith ethyl acetate. The organic phase was dried over magnesium sulphate,filtered and evaporated to dryness. The residual oil was purified bycolumn chromatography on silica gel using a 47:3 mixture of methylenechloride and methanol as eluent to yieldN-(3-morpholinobenzoyl)morpholine (0.45 g).

A mixture of N-(3-morpholinobenzoyl)morpholine (0.45 g), 5M sodiumhydroxide solution (2.5 ml) and butanol (2 ml) was stirred and heated to115° C. for 18 hours. The mixture was evaporated to dryness and theresidue was acidified by the addition of 1M hydrochloric acid solution(12.5 ml). The resultant precipitate was isolated, washed with water anddried to yield 3-morpholinobenzoic acid (0.15 g); NMR: 3.1 (t, 4H), 3.73(t, 4H), 7.19 (d, 1H), 7.32 (d, 1H), 7.38 (t, 1H), 7.42(s, 1H).

Oxalyl chloride (0.14 ml) was added to a solution of 3-morpholinobenzoicacid (0.28 g) in methylene chloride (10 ml) which containedN,N-dimethylformamide (2 drops). The reaction mixture was stirred for 18hours at ambient temperature. The mixture was evaporated and azeotropedwith toluene to yield 3-morpholinobenzoyl chloride (0.3 g); M/z M+H⁺222.

3-Morpholinobenzoyl chloride (6.22 g) was added to a solution of4-methyl-3-nitroaniline (4.20 g) and triethylamine (11.0 ml) inmethylene chloride (150 ml) at ambient temperature under argon. Thereaction mixture was stirred for 18 hours then diluted to 250 ml withmethylene chloride. The mixture was washed with water (3×150 ml) andsaturated sodium bicarbonate solution (2×100 ml), dried and evaporatedto give a dark brown oil. The oil was triturated with diethyl ether andthe solid collected and dried to yieldN-(4-methyl-3-nitrophenyl)-3-morpholinobenzamide (1.82g); NMR: (CDCl₃)2.53 (s, 3H), 3.22 (t, 4H), 3.83 (t, 4H), 7.06 (dd, 1H), 7.23 (d, 1H),7.37 (m, 2H), 7.42 (d, 1H), 7.88 (dd, 1H), 7.97 (s, 1H), 8.21 (d, 1H);m/z 340 (MH⁺); m.p. 149-150° C.

10% palladium on carbon (150 mg) was added to a stirred suspension ofN-(3-nitro-4-methylphenyl)-3-morpholinobenzamide (1.40 g) in ethanol(100 ml) under argon. The argon atmosphere was replaced with hydrogenand the mixture was stirred at ambient temperature for 4 hours. Thecatalyst was removed by filtration through diatomaceous earth (Celite®)and the residue washed with methylene chloride. The filtrate wasevaporated to give a solid which was triturated with ethyl acetate toyield N-(3-amino-4-methylphenyl)-3-morpholinobenzamide (1.02 g); NMR:2.0 (s, 3H), 3.19 (t, 4H), 3.78 (t, 4H), 4.8 (s, 2H), 6.8 (m, 2H), 7.08(s, 1H), 7.11 (d, 1H), 7.34 (m, 2H), 7.4 (s, 1H), 9.8 (s, 1H); m/z 312.

r) The product was purified by column chromatography, eluting with89:10:1 methylene chloride/methanol/aqueous ammonia solution, relevantfractions concentrated and triturated with methylene chloride. Theproduct gave the following data: NMR: 2.13 (s, 3H), 3.51 (m, 4H), 3.7(m, 4H), 3.92 (2s, 6H), 7.09 (m, 1H), 7.15 (s, 1H), 7.23 (m, 1H) 7.29(m, 1H), 7.59 (m, 1H), 7.77 (m, 1H), 7.83 (s, 1H), 8.26 (m, 2H), 9.39(s, 1H) 10.28 (s, 1H); Mass: M+H⁺ 501.

The N-(3-amino-4-methylphenyl)-2-morpholinopyridine-4-carboxamide usedas a starting material was prepared as follows:

4-Methyl-3-nitroaniline (15.8 g) and 2-chloropyridine-4-carbonylchloride (20 g) were stirred in methylene chloride (1000 ml) followed bytriethylamine (31.8 ml) and stirred at ambient temperature for 72 hours.Reaction was filtered, washed with saturated sodium bicarbonate andmethylene chloride and dried in a vacuum oven affording a solid (10.2g). The original filtrate was washed with saturated sodium bicarbonate.Organic layer was evaporated and then methylene chloride (50 ml) wasadded and the solid filtered and dried in a vacuum oven to yield2-chloro-N-(4-methyl-3-nitrophenyl)pyridine-4-carboxamide (8.13 g); NMR:2.48 (s, 3H), 7.51 (d, 1H), 7.86 (m, 1H), 7.96 (m, 2H), 8.49 (m, 1H),8.64 (m, 1H) 10.85 (s, 1H); m/s: M+H⁺ 292, 294.

2-Chloro-N-(4-methyl-3-nitrophenyl)pyridine-4-carboxamide (18.33 g) wasstirred in morpholine (250 ml) at 100° C. for 18 hours. Reaction waspoured into water (250 ml) affording a gummy solid. Methylene chloride(30 ml) was added and stirred for 30 minutes and solid filtered, washedwith methylene chloride and dried in a vacuum oven for 18 hours to yieldN-(4-methyl-3-nitrophenyl)-2-morpholinopyridine-4-carboxamide the titlecompound (17.34 g); NMR: 2.48 (s, 3H), 3.52 (m, 4H), 3.71 (m, 4H), 7.1(d, 1H), 7.25 (s, 1H), 7.49 (d, 1H), 7.97 (m, 1H), 8.29 (m, 1H), 8.49(m, 1H), 10.62 (s, 1H); m/s: M+H⁺ 343.

Under argon, 5% palladium on carbon (850 mg) was added toN-(4-methyl-3-nitrophenyl)-2-morpholinopyridine-4-carboxamide (8.5 g) inmethanol (300 ml). Hydrogen gas was introduced to the reaction via aballoon and stirred at ambient temperature for 18 hours. Methanol (200ml) was added and the reaction mixture was filtered through celite. Thefiltrate was evaporated, then stirred in ethyl acetate, filtered againand washed with a small amount of methanol to yieldN-(3-amino-4-methylphenyl)-2-morpholinopyridine-4-carboxamide (5.12 g);NMR: 2.01 (s, 3H), 3.52 (m, 4H), 3.73 (m, 4H), 4.83 (s, 2H), 6.78 (d,1H), 6.84 (d, 1H) 7.04-7.08 (m, 2H), 7.20 (s, 1H), 8.24 (d, 1H), 9.95(s, 1H); m/s: M+H⁺ 313.

Example 46 4-[3-Benzamido-4-fluoroanilino]-6,7-dimethoxyquinolinehydrochloride

Using an analogous procedure to that described in Example 26,4-chloro-6,7-dimethoxyquinoline was reacted withN-(5-amino-2-fluorophenyl)benzamide to give the title compound; NMR:3.98 (s, 3H), 4.0 (s, 3H), 6.73 (d, 1H), 7.34 (m, 1H), 7.43 (s, 1H),7.46 (d, 1H), 7.55 (m, 4H), 7.82 (dd, 1H), 7.98 (d, 2H), 8.13 (s, 1H),8.37 (d, 1H), 10.32 (broad s, 1H), 10.67 (broad s, 1H); Mass: M+H⁺ 418.

Example 47 4-[3-Benzamido-4-fluoroanilino]-4,7,8-trimethoxyquinazolinehydrochloride

N-(2-Fluoro-5-aminophenyl)benzamide (276 mg) was added to a suspensionof 4-chloro-6,7,8-trimethoxyquinazoline hydrochloride (293 mg) inisopropanol (8 ml) and the resultant mixture stirred and heated to 80°C. for 18 hours. The mixture was cooled to ambient temperature and theprecipitated solid was isolated, washed with isopropanol then diethylether to yield the title compound as a solid (257 mg, 53%); NMR: 4.0 (s,3H), 4.01 (s, 3H), 4.07 (s, 3H), 7.42 (t, 1H), 7.52 (m, 2H), 7.62 (m,2H), 8.0 (m, 3H), 8.35 (s, 1H), 8.72 (s, 1H), 10.28 (s, 1H), 11.84(broad s, 1H); m/s: M+H⁺ 449.

Example 484-[2-Methyl-5-(3-dimethylaminobenzamido)anilino]-6,7-dimethoxyquinoline

4-Chloro-6,7-dimethoxyquinoline (WO 98/13350 A1) (150 mg) andN-(3-amino-4-methylphenyl)-3-dimethylaminobenzamide (199 mg) werestirred in isopropanol (5 ml) and heated to 85° C. for 18 hours. Aftercooling to room temperature the precipitated solid was isolated andwashed with isohexane. Filtered solid was impure and so was purified byeluting through a silica column with 10% methanol in methylene chloride.The title compound was obtained as a solid (35 mg); NMR: 2.14 (s, 3H),2.94 (s, 6H), 3.89 (s, 3H), 3.93 (s, 3H), 6.05 (m, 1H), 6.90 (m, 1H),7.18 (m, 1H), 7.22 (m, 1H), 7.3 (m, 1H), 7.61 (m, 1H), 7.73 (s, 1H),7.78 (m, 1H), 8.18 (d, 1H), 8.47 (s, 1H), 10.1 (s, 1H); m/s: M+H⁺ 457.

Example 494-[2-Methyl-5-(3,4-dimethoxybenzamido)anilino]-6,7-dimethoxyquinolinehydrochloride

Hydrochloric acid (0.15 ml) was added to a mixture of4-chloro-6,7-dimethoxy quinoline (335 mg) andN-(3-amino-4-methylphenyl)-3,4-dimethoxybenzamide (472 mg) inisopropanol (8 ml) and heated to 85° C. for 18 hours. After cooling toroom temperature the precipitated solid was isolated and washed withisohexane to yield the title compound as a solid (180 mg, 24%); NMR:2.31 (s, 3H), 3.82 (s, 6H), 3.97 (s, 3H), 3.99 (s, 3H), 6.75 (m, 1H),7.06 (m, 1H), 7.25 (m, 1H), 7.42 (m, 2H), 7.51 (m, 1H), 7.55 (m, 1H),7.64 (m, 1H), 8.1 (s, 1H), 8.36 (m, 1H), 9.84 (s, 1H), 10.61 (s, 1H);m/s: M+H⁺ 474.

Example 504-[3-(3,4-Dimethoxybenzamido)-4-methylanilino]-6,7-dimethoxyquinolinehydrochloride

4-Chloro-6,7-dimethoxyquinoline (315 mg) andN-(2-methyl-5-aminophenyl)-3,4-dimethoxybenzamide (443 mg) were stirredtogether in isopropanol (10 ml) and heated to 85° C. for 18 hours. Aftercooling to room temperature the precipitated solid was isolated andwashed with isohexane to yield the title compound as a solid (260 mg,36%); NMR: 2.32 (s, 3H), 3.82 (s, 6H), 3.97 (s, 3H), 3.99 (s, 3H), 6.75(m, 1H), 7.07 (m, 1H), 7.25 (m, 1H), 7.46 (m, 2H), 7.51 (m, 1H), 7.58(m, 1H), 7.64 (m, 1H), 8.1 (s, 1H), 8.36 (m, 1H), 9.85 (s, 1H), 10.62(s, 1H); m/s: M+H⁺ 474.

The N-(5-amino-2-methylphenyl)-3,4-dimethoxybenzamide used as a startingmaterial was prepared as follows:

A solution of 3,4-dimethoxybenzoyl chloride (11.5 g) in methylenechloride (100 ml) was added dropwise to a stirred mixture of2-methyl-5-nitroaniline (8.74 g), pyridine (18.6 ml) and methylenechloride (200 ml) and the mixture was stirred at ambient temperature for18 hours. The mixture was washed with 2M hydrochloric acid and withwater, dried over magnesium sulphate, filtered and evaporated todryness. The resultant solid was dried under vacuum at 60° C. to yieldN-(2-methyl-5-nitrophenyl)-3,4-dimethoxybenzamide (15.9 g); m.p.>300°C.; NMR: (CDCl₃) 2.43 (s, 3H), 3.94 (m, 6H), 6.93 (m, 1H), 7.38 (m, 2H),7.51 (m, 1H), 7.75 (broad s, 1H), 7.94 (d, 1H), 8.89 (broad m, 1H).

10% Palladium-on-carbon (4 g) was added to a stirred suspension ofN-(2-methyl-5-nitrophenyl)-3,4-dimethoxybenzamide (15.9 g) in methanol(1500 ml) and the mixture was stirred under an atmosphere of hydrogengas. After cessation of hydrogen uptake, the catalyst was removed byfiltration and the filtrate was evaporated. The residue was washed withdiethyl ether and dried under vacuum at 60° C. to yield the requiredcompound (11.3 g); m.p. 157-158° C.; NMR: (CDCl₃) 2.24 (s, 3H), 3.64(broad s, 2H), 3.95 (m, 6H), 6.44 (m, 1H), 6.93 (d, 1H), 6.98 (d, 1H),7.38 (m, 1H), 7.54 (m, 2H), 7.6 (broad s, 1H).

Example 51 4-(3-Acetamidoanilino)-6,7-dimethoxyquinoline hydrochloride

The title compound was prepared using the method of Example 50 and theappropriate starting materials; NMR: 2.09 (s, 3H), 3.99 (s, 3H), 4.01(s,3H), 6.75 (d, 1H), 7.13 (dt, 1H), 7.48 (m, 3H), 7.89 (s, 1H), 8.15 (s,1H), 8.35 (d, 1H), 10.32 (br s, 1H), 10.67 (br s, 1H), 14.33 (br s, 1H);m/z 338.

Example 526-Acetoxy-7-methoxy-4-[2-methyl-5-(2-morpholinopyridine-4-carboxamido)anilino]quinazolinedihydrochloride

A mixture ofN-(3-amino-4-methylphenyl)-2-morpholinopyridine-4-carboxamide (178 mg),6-acetoxy-4-chloro-7-methoxyquinazoline hydrochloride (150 mg) andisopropanol (5 ml) was stirred and heated to 85° C. for 3 hours. Thereaction mixture was allowed to cool to ambient temperature and thesolid was isolated and washed in turn with isopropanol (5 ml) andisohexane (2×5 ml). There was thus obtained the title compound (249 mg,80%); NMR: 2.17 (s, 3H), 2.38 (s, 3H), 3.56 (m, 4H), 3.72 (m, 4H), 4.0(s, 3H), 7.16 (m, 1H), 7.37 (m, 2H), 7.52 (s, 1H), 7.68 (m, 1H), 7.87(m, 1H), 8.24 (m, 1H), 8.67 (s, 1H), 8.8 (s, 1H), 10.6 (s, 1H), 11.50(s, 1H); m/s: M+H⁺ 529.

The 6-acetoxy-4-chloro-7-methoxyquinazoline hydrochloride used as astarting material was prepared as follows:

A mixture of 6-acetoxy-7-methoxyquinazolin-4-one (International PatentApplication WO 96/15118, Example 39 thereof; 4.1 g), thionyl chloride(75 ml) and dimethylformamide (0.2 ml ) was stirred and heated to 90° C.for 6 hours. The mixture was evaporated and the residue was azeotropedwith toluene. There was thus obtained the required compound as a solid(4.6 g); NMR: 2.3 (s, 3H), 3.94 (s, 3H), 7.4 (s, H), 7.83 (s, 1H), 8.68(s, 1H); m/s: M+H⁺ 253, 255.

Example 536-Hydroxy-7-methoxy-4-[2-methyl-5-(2-morpholinopyridine-4-carboxamido)anilino]quinazoline

A mixture of6-acetoxy-7-methoxy-4-[2-methyl-5-(2-morpholinopyridine-4-carboxamido)anilino]quinazolinedihydrochloride (150 mg) and methanolic ammonia (2 ml) was stirred andheated to 50° C. for 48 hours. The mixture was allowed to cool toambient temperature and the resultant solid was isolated and washed withdiethyl ether (10 ml). There was thus obtained the title compound (95mg, 78%); NMR: 2.12 (s, 3H), 3.51 (m, 4H), 3.7 (m, 4H), 3.97 (s, 3H),7.09 (m, 1H), 7.12 (s, 1H), 7.23 (m, 2H), 7.57 (m, 1H), 7.69 (s, 1H),7.72 (m, 1H), 8.23 (s, 1H), 8.26 (m, 1H), 9.17 (s, 1H), 10.28 (s, 1H);m/s: M+H⁺ 487.

Example 546-(N,N-Diethylcarbamoylmethoxy)-7-methoxy-4-[2-methyl-5-(2-morpholinopyridine-4-carboxamido)anilino]quinazoline

2-Chloro-N,N-diethylacetamide (0.05 g) was added to a mixture of6-hydroxy-7-methoxy-4-[2-methyl-5-(2-morpholinopyridine-4-carboxamido)anilino]quinazoline(0.15 g), cesium carbonate (0.3 g) and dimethylacetamide (2 ml) and thereaction mixture was stirred and heated to 100° C. for 18 hours. Aftercooling to ambient temperature the reaction mixture was partitionedbetween methylene chloride and water. The organic layer was dried withbrine and sodium sulphate, filtered and evaporated. The residual gum wastriturated under diethyl ether. There was thus obtained the titlecompound as a solid (0.04 g, 20%); NMR: 1.05 (t, 3H), 1.4 (t, 3H), 2.13(s, 3H), 3.35 (m, 4H), 3.51 (m, 4H), 3.7 (m, 4H), 3.95 (s, 3H), 4.91 (s,2H), 7.11 (m, 1H), 7.18 (s, 1H), 7.24 (s, 1H), 7.29 (m, 1H), 7.6 (m,1H), 7.77 (m, 2H), 8.26 (m, 2H), 9.3 (broad s, 1H), 10.32 (broad s, 1H);m/s: M+H⁺ 600.

Examples 55-72

Using an analogous procedure to that described in Example 54,6-hydroxy-7-methoxy-4-[2-methyl-5-(2-morpholinopyridine-4-carboxamido)anilino]quinazolinewas reacted with the appropriate alkyl chloride to give the compoundsdescribed in the following table. Unless otherwise stated, eachappropriate alkyl chloride is either commercially available or isreadily prepared by standard methods from known materials.

Ex. No. R R² R³ Note 55 N,N-dimethylcarbamoylmethoxy Me H a) 562-dimethylaminoethoxy Me H b) 57 2-diethylaminoethoxy Me H c) 582-diisopropylaminoethoxy Me H d) 59 3-dimethylaminopropoxy Me H e) 603-diethylaminopropoxy Me H f) 61 2-dimethylamino-2-methylpropoxy Me H g)62 2-(pyrrolidin-1-yl)ethoxy Me H h) 63 2-piperidinoethoxy Me H i) 642-morpholinoethoxy Me H j) 65 3-(pyrrolidin-1-yl)propoxy Me H k) 663-morpholinopropoxy Me H l) 67 3-(4-methylpiperazin-1-yl)propoxy Me H m)68 2-(N-methylpyrrolidin-2-yl)ethoxy Me H n) 69N-methylpiperidin-2-ylmethoxy Me H o) 70 N-methylpiperidin-3-ylmethoxyMe H p) 71 N-methyl-5-oxopiperidin-2-ylmethoxy Me H q) 722-(2-oxoimidazolidin-1-yl)ethoxy Me H r) Notes a) The product gave thefollowing data: NMR: 2.15(s, 3H), 2.92(s, 3H), 3.06(s, 3H), 3.53(m, 4H),3.7(m, 4H), 3.93(s, 3H), 4.92(s, 2H), 7.1(m, 1H), 7.18(s, 1H), 7.27(m,2H), 7.59(m, 1H), 7.75(m, 1H), 8.29(m, 2H), 9.8(broad s, 1H); Mass: M+H⁺572. b) The product gave the following data: Mass: M+H⁺ 558. c) Theproduct gave the following data: Mass: M+H⁺ 586. d) The product gave thefollowing data: NMR: 0.95(m, 12H), 2.17(s, 3H), 2.88(s, 2H), 3.04(m,2H), 3.5(m, 4H), 3.7(m, 4H), 3.93(s, 3H), 4.0(m, 2H), 7.1(m, 1H),7.17(s, 1H), 7.24(s, 1H), 7.29(m, 1H), 7.59(m, 1H), 7.77(m, 1H), 7.82(s,1H), 8.28(m, 2H), 9.42(broad s, 1H), 10.32(broad s, 1H); Mass: M+H⁺ 614.e) The product gave the following data: Mass: M+H⁺ 572. f) The productgave the following data: Mass: M+H⁺ 600. g)2-Dimethylamino-2-methylpropyl chloride (Chemical Abstracts, volume 58,no. 4477a) was used as the appropriate alkyl chloride. The product gavethe following data: Mass: M+H⁺ 586.

The 2-dimethylamino-2-methylpropyl chloride hydrochloride used as astarting material was prepared as follows:

A solution of 2-dimethylamino-2-methylpropan-1-ol (12.78 g) in toluene(100 ml) was dried azeotropically by concentration under reducedpressure to a volume of 50 ml. Thionyl chloride (8.8 ml) was addedgradually and the mixture was stirred and heated to 80° C. for 2.5hours. The mixture was cooled to ambient temperature and evaporated. Thesolid residue was washed with diethyl ether. There was thus obtained therequired compound (10.5 g); NMR: (CDCl₃) 1.61 (s, 6H), 2.83 (s, 3H),2.86 (s, 3H), 3.86 (s, 2H), 12.52 (broad s, 1H); Mass: M+H⁺ 136.

h) The product gave the following data: Mass: M+H⁺ 584.

i) The product gave the following data: NMR: 1.3-1.6 (broad m, 6H), 2.15(s, 3H), 2.79 (m, 2H), 3.53 (m, 4H), 3.7 (m, 4H), 3.93 (s, 3H), 4.2 (t,2H), 7.1 (m, 1H), 7.18 (s, 1H), 7.25 (s, 1H), 7.29 (m, 1H), 7.6 (m, 1H),7.79 (m, 1H), 7.86 (m, 1H), 8.27 (m, 2H), 9.37 (broad s, 1H), 10.28(broad s, 1H); Mass: M+H⁺ 598.

j) The product gave the following data: Mass: M+H⁺ 600.

k) 3-(Pyrrolidin-1-yl)propyl chloride (Chemical Abstracts, volume 128,no. 227441; PCT Patent Application WO 9813354) was used as theappropriate alkyl chloride. The product gave the following data: NMR:1.68 (m, 4H), 1.99 (m, 2H), 2.16 (s, 3H), 2.48 (m, 4H), 2.58 (m, 2H),3.53 (m, 4H), 3.72 (m, 4H), 3.92 (s, 3H), 4.18 (m, 2H), 7.09 (d, 1H)7.15 (s, 1H), 7.23 (s, 1H), 7.28 (d, 1H), 7.58 (d, 1H), 7.76 (s, 1H),7.82 (s, 1H), 8.27 (m, 2H), 9.38 (s, 1H), 10.28 (s, 1H); Mass: M+H⁺ 598.

l) The product gave the following data: NMR: 2.0 (broad m, 2H), 2.15 (s,3H), 2.4 (m, 2H), 3.53 (m, 12H), 3.7 (m, 4H), 3.93 (s, 3H), 4.15 (t,2H), 7.1 (m, 1H), 7.18 (s, 1H), 7.25 (s, 1H), 7.29 (m, 1H), 7.59 (m,1H), 7.77 (m, 1H), 7.83 (m, 1H), 8.27 (m, 2H), 9.39 (broad s, 1H), 10.28(broad s, 1H); Mass: M+H⁺ 614.

m) The product gave the following data: NMR: 1.98 (m, 2H), 2.15 (2s,6H), 2.25-2.5 (broad m, 10H), 3.52 (m, 4H), 3.70 (m, 4H), 3.94 (s, 3H),4.15 (broad t, 2H), 7.1 (m, 1H), 7.15 (s, 1H), 7.23 (s, 1H), 7.29 (m,1H), 7.59 (m, 1H), 7.78 (m, 1H), 7.82 (m, 1H), 8.27 (m, 2H), 9.38 (broads, 1H), 10.29 (broad s, 1H); Mass: M+H⁺ 627.

n) The product gave the following data: Mass: M+H⁺ 598.

o) N-Methylpiperidin-2-ylmethyl chloride (Chem. Pharm. Bull., 1965,13(3), 241-247) was used as the appropriate alkyl chloride. The productgave the following data: NMR: 1.6-1.7 (m, 6H), 2.17 (s, 3H), 2.34 (s,3H), 2.7-2.9 (m, 3H), 3.51 (m, 4H), 3.7 (m, 4H), 3.91 (s, 3H), 3.99 (m,1H), 4.22 (m, 1H), 7.1 (d, 1H), 7.15 (s, 1H), 7.22 (s, 1H), 7.28 (d,1H), 7.59 (m, 1H), 7.75 (s, 1H), 7.83 (s, 1H), 8.26 (m, 2H), 9.33 (d,1H), 10.28 (s, 1H); Mass: M+H⁺ 598.

The 1-methylpiperidin-2-ylmethyl chloride hydrochloride used as astarting material was prepared as follows:

Hydrogen chloride gas was bubbled into a solution of1-methyl-2-piperidinemethanol (12.9 g) in chloroform (80 ml) until twolayers developed. The resultant mixture was heated to reflux and thionylchloride (29 ml) was added slowly. The mixture was stirred and heated toreflux for a further hour. The mixture was evaporated, ethanol was addedand the mixture was re-evaporated. The residue was dissolved in ethanoland the solution was decolourised with charcoal. The clear filtrate wasdiluted with diethyl ether until turbidity occurred. The requiredcompound (12 g) crystallised from the solution; m.p. 159-162° C.; Mass:M+H⁺ 147.

p) The product gave the following data: Mass: M+H⁺ 598.

q) N-Methyl-5-oxopyrrolidin-2-ylmethyl chloride (Chemical Abstracts,volume 89, no. 163329; J. Org. Chem., 1978, 43, 3750) was used as theappropriate alkyl chloride. The product gave the following data: Mass:M+H⁺ 598.

r) 2-(2-Oxoimidazolidin-1-yl)ethyl chloride (Chemical Abstracts, volume125, no. 221856; UK Patent Application No. 2295387) was used as theappropriate alkyl chloride. The product gave the following data: Mass:M+H⁺ 599.

Example 736-Methoxy-7-(N-methylpiperidin-3-ylmethoxy)-4-[2-methyl-5-(2-morpholinopyridine-4-carboxamido)anilino]quinazoline

Using an analogous procedure to that described in Example 26 except that3 equivalents of the 1M solution of hydrogen chloride in diethyl etherwere used.4-chloro-6-methoxy-7-(N-methylpiperidin-3-ylmethoxy)quinazoline wasreacted withN-(3-amino-4-methylphenyl)-2-morpholinopyridine-4-carboxamide. Thereaction product was purified by column chromatography on silica usingan 89:10:1 mixture of methylene chloride, methanol and a saturatedaqueous ammonium hydroxide solution as eluent. There was thus obtainedthe title compound in 34% yield; NMR: 1.12 (m, 1H), 1.52 (m, 1H),1.65-2.05 (broad, 3H), 2.15 (s, 3H), 2.2 (s, 3H), 2.7 (m, 2H), 2.90 (m,2H), 3.53 (m, 4H), 3.73 (m, 4H), 3.95 (s, 3H), 4.04 (d, 2H), 7.1 (m,1H), 7.16 (s, 1H), 7.24 (m, 1H), 7.31 (m, 1H), 7.59 (m, 1H), 7.78 (m,1H), 7.84 (s, 1H), 8.27 (m, 2H), 9.4 (s, 1H), 10.3 (s, 1H); m/s: M+H⁺598.

The 4-chloro-6-methoxy-7-(N-methylpiperidin-3-ylmethoxy)quinazoline usedas a starting material was prepared as follows:

A mixture of 7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one (20.3 g),thionyl chloride (440 ml) and DMF (1.75 ml) was stirred and heated toreflux for 4 hours. The thionyl chloride was evaporated and the residuewas azeotroped with toluene three times to give crude7-benzyloxy-4-chloro-6-methoxyquinazoline.

A mixture of the crude 7-benzyloxy-4-chloro-6-methoxyquinazoline,4-chloro-2-fluorophenol (8.8 ml, 83 mmol), potassium carbonate (50 g,362 mmol) and DMF (500 ml) was stirred and heated to 100° C. for 5hours. The mixture was allowed to cool to ambient temperature. Thereaction mixture was poured into water (2 L) and the resultant mixturewas stirred at ambient temperature for a few minutes. The solid soobtained was isolated and washed with water. The resultant solid wasdissolved in methylene chloride and filtered through diatomaceous earth.The filtrate was treated with decolourising charcoal, boiled for a fewminutes and then filtered through diatomaceous earth. The filtrate wasfiltered through phase separating paper and evaporated under vacuum togive a solid residue which was triturated under diethyl ether, isolatedand dried. There was thus obtained7-benzyloxy-4-(4-chloro-2-fluorophenoxy)-6-methoxyquinazoline (23.2 g,76%); NMR: (DMSOd₆) 3.98 (s, 3H), 5.34 (s, 2H), 7.42 (m, 9H), 7.69 (m,1H), 8.55 (s, 1H).

A mixture of7-benzyloxy-4-(4-chloro-2-fluorophenoxy)-6-methoxyquinazoline (23 g) andtrifluoroacetic acid (150 ml) was stirred and heated to reflux for 3hours. The reaction mixture was allowed to cool to ambient temperature.Toluene was added and the mixture was evaporated. The residue wastriturated under diethyl ether and then under acetone. The precipitatewas collected by filtration and dried to give4-(4-chloro-2-fluorophenoxy)-7-hydroxy-6-methoxyquinazoline (19 g) whichwas used without further purification; NMR: (DMSOd₆) 3.97 (s, 3H), 7.22(s, 1H), 7.39 (d, 1H), 7.53 (m, 2H), 7.67 (m, 1H), 8.46 (s, 1H).

A mixture of 4-(4-chloro-2-fluorophenoxy)-7-hydroxy-6-methoxyquinazoline(12.1 g), triphenylphosphine (29.6 g) and methylene chloride (375 ml)was stirred at ambient temperature for 30 minutes. The reaction mixturewas cooled in an ice-bath and a solution ofN-methylpiperidin-3-ylmethanol (8.25 g) in methylene chloride (75 ml)was added followed by the portionwise addition of diethylazodicarboxylate (17.7 ml). The reaction mixture was allowed to warm toambient temperature and was stirred overnight. The mixture wasconcentrated under vacuum and the residue was purified by columnchromatography on silica using initially methylene chloride and then a93:6:1 mixture of methylene chloride, methanol and an aqueous ammoniumhydroxide solution as eluent. The material so obtained was trituratedunder diethyl ether. There was thus obtained4-(4-chloro-2-fluorophenoxy)-6-methoxy-7-(N-methylpiperidin-3-ylmethoxy)quinazoline(8.7 g, 53%); NMR: (DMSOd₆) 1.11 (m, 1H), 1.5 (m, 1H), 1.58-1.98 (m,4H), 2.09 (m, 1H), 2.15 (s, 3H), 2.62 (d, 1H), 2.81 (d, 1H), 3.95 (s,3H), 4.09 (d, 2H), 7.39 (m, 2H), 7.55 (m, 2H), 7.67 (d, 1H), 8.53 (s,1H); Mass: M+H⁺ 432.

4-(4-Chloro-2-fluorophenoxy)-6-methoxy-7-(N-methylpiperidin-3-ylmethoxy)quinazoline(8.7 g, 20 mmol) was dissolved in 2M aqueous hydrochloric acid (150 ml)and the mixture was stirred and heated to reflux for 1.5 hours. Thereaction mixture was concentrated by evaporation under vacuum and theresidue was basified to pH9 by the addition of saturated aqueousammonium hydroxide solution. The aqueous layer was extracted withmethylene chloride (4×400 ml). The combined organic extracts werefiltered through phase-separating paper and evaporated. The solid soobtained was triturated under diethyl ether to give6-methoxy-7-(N-methylpiperidin-3-ylmethoxy)-3,4-dihydroquinazolin-4-one(4.05 g, 66%) as a white solid; NMR: (DMSOd₆) 1.05 (m, 1H), 1.40-1.95(m, 5H), 2.02 (m, 1H), 2.14 (s, 3H), 2.59 (d, 1H), 2.78 (d, 1H), 3.85(s, 3H), 3.95 (d, 2H), 7.09 (s, 1H), 7.42 (s, 1H), 7.95 (s, 1H), 12.0(s, 1H); Mass: M+H⁺ 304.

A mixture of6-methoxy-7-(N-methylpiperidin-3-ylmethoxy)-3,4-dihydroquinazolin-4-one(2.72 g, 8.9 mmol), thionyl chloride (90 ml) and DMF (0.5 ml) wasstirred and heated to reflux for 45 minutes. The mixture was evaporatedand the residue was azeotroped with toluene. The residue was taken up inwater and basified to pH8 by the addition of a saturated aqueous sodiumhydrogen carbonate solution. The aqueous layer was extracted with ethylacetate (4×400 ml). The combined organic extracts were washed in turnwith a saturated aqueous sodium hydrogen carbonate solution, water andbrine, dried (MgSO₄) and evaporated. The residue was dried overnight at40° C. under vacuum to give4-chloro-6-methoxy-7-(N-methylpiperidin-3-ylmethoxy)quinazoline (2.62 g,91%) as a solid; NMR: (DMSOd₆) 1.1 (m, 1H), 1.42-1.96 (m, 5H), 2.09 (m,1H), 2.15 (s, 3H), 2.6 (d, 1H), 2.8 (d, 1H), 3.98 (s, 3H), 4.1 (d, 2H),7.35 (s, 1H), 7.42 (s, 1H), 8.84 (s, 1H); Mass: M+H⁺ 322.

Example 744-[5-(4-Cyanobenzamido)-2-methylanilino]-6-methoxy-7-(3-morpholinopropoxy)quinazoline

Using an analogous procedure to that described in Example 26,4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline was reacted withN-(3-amino-4-methylphenyl)-4-cyanobenzamide to give the title compoundin 52% yield; NMR: 2.15 (s, 3H), 2.3 (m, 2H), 3.0-4.1 (broad m, 10H),3.95 (s, 3H), 4.3 (m, 2H), 7.35 (m, 2H), 7.65 (m, 1H), 7.88 (m, 1H),8.02 (m, 2H), 8.14 (m, 3H), 8.53 (s, 1H), 10.65 (s, 1H), 12.1 (s, 1H);m/s: M+H⁺ 553.

The 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline used as astarting material was prepared as follows:

Sodium hydride (60% dispersion in oil, 0.53 g) was added to a solutionof 7-benzyloxy-6-methoxy-4-quinazalone (3.0 g) in dry dimethylformamide(25 ml) and stirred under vacuum for 1 hour. Chloromethyl pivalate (1.96ml) was added under argon dropwise over 10 minutes and reaction allowedto stir at ambient temperature for 48 hours. Ethyl acetate (25 ml) wasadded and whole reaction mixture was poured into water. 2M Hydrochloricacid (1.0 ml) was added followed by more ethyl acetate (40 ml) and thereaction was stirred vigorously for 0.5 hour. The resulting solid wasfiltered, washed with diethyl ether and dried under vacuum for 18 hours.(3.16 g). The filtrate was extracted with ethyl acetate (3×75 ml). Theorganic phases were combined and washed with water and then brine, driedover magnesium sulphate, filtered and evaporated to dryness. The residuewas triturated with diethyl ether. There was thus obtained7-benzyloxy-6-methoxy-3-pivaloyloxymethyl-3,4-dihydroquinazolin-4-one asa solid (1.01 g; overall yield: 4.17 g, 99%); NMR: 1.11 (s, 9H), 3.91(s, 3H), 5.27 (s, 2H), 5.91 (s, 2H), 7.24 (s, 1H), 7.43 (m, 6H), 8.34(s, 1H); m/s: M+H⁺ 397.

10% palladium on carbon (420 mg) was added to a solution of7-benzyloxy-6-methoxy-3-pivaloyloxymethyl-3,4-dihydroquinazolin-4-one(4.17 g) in dimethylformamide (30 ml), methanol (30 ml), ethyl acetate(150 ml) and acetic acid (0.42 ml). Hydrogen gas was bubbled into thereaction and it was then stirred at ambient temperature for 18 hours.Reaction was poured through diatomaceous earth (Celite®) and thefiltrate was evaporated to dryness and then triturated with diethylether and dried to yield7-hydroxy-6-methoxy-3-pivaloyloxymethyl-3,4-dihydroquinazolin-4-one as asolid, (2.51 g, 78%). NMR: 1.10 (s, 9H), 3.88 (s, 3H), 5.86 (s, 2H),6.96 (s, 1H), 7.46 (s, 1H), 8.29 (s, 1H); m/s: M+H⁺ 307.

Potassium carbonate (4.51 g) was added to7-hydroxy-6-methoxy-3-pivaloyloxymethyl-3,4-dihydroquinazolin4-one (2.0g) in dimethylformamide (50 ml) followed by 3-morpholinopropyl chloride(1.3 g) and the reaction was stirred at 100° C. for 6 hours. Aftercooling the solid was removed by filtration and the filtrate wasevaporated and was purified by eluting through a silica column with 10%methanol in methylene chloride to yield6-methoxy-7-(3-morpholinopropoxy)-3-pivaloyloxymethyl-3,4-dihydroquinazolin-4-oneas a solid (1.85 g, 65%); NMR: 1.1 (s, 9H), 1.9 (m, 2H), 2.4 (broad m,6H), 3.55 (m, 4H), 3.88 (s, 3H), 4.16 (m, 2H), 5.89 (s, 2H), 7.13 (s,1H), 7.47 (s, 1H), 8.32 (s, 1H); m/s: M+H⁺ 434.

6-Methoxy-7-(3-morpholinopropoxy)-3-pivaloyloxymethyl-3,4-dihydroquinazolin-4-one(1.85 g) was stirred in methylene chloride (20 ml) and methanol (20 ml)and methanolic ammonia (2M, 100 ml) was added. The reaction was stirredat ambient temperature for 48 hours, evaporated to dryness, and thenstirred in diethyl ether for 1 hour. The reaction mixture was filteredaffording 6-methoxy-7-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-oneas a solid, (1.22 g, 90%); NMR: 1.9 (m, 2H), 2.4 (broad m, 6H), 3.55 (m,4H), 3.88 (s, 3H), 4.12 (m, 2H), 7.1 (s, 1H), 7.41 (s, 1H), 7.94 (s,1H); m/s: M+H⁺ 320.

6-Methoxy-7-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one (1.22 g)was stirred in thionyl chloride (10 ml) with dimethylformamide (0.1 ml)at 85° C. for 1 hour. The reaction was evaporated to dryness, and thenazeotroped with toluene. The residue was partitioned between methylenechloride and saturated sodium bicarbonate. The organic phase wasseparated and evaporated to dryness. The saturated sodium bicarbonatephase was basified with 2M sodium hydroxide and was extracted withmethylene chloride. The two organic phases were combined and dried oversodium sulphate, filtered and the filtrate evaporated to dryness. Thisresidue was purified by eluting through a silica column with 5% methanolin methylene chloride to yield4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline as a solid, (0.5g, 39%); NMR: 1.95 (m, 2H), 2.4 (broad m, 6H), 3.55 (m, 4H), 3.98 (s,3H), 4.26 (t, 2H), 7.36 (s, 1H), 7.41 (s, 1H), 8.83 (s, 1H); m/s: M+H⁺338, 340.

Example 756-Methoxy-4-[2-methyl-5-(2-morpholinopyridine-4-carboxamido)anilino]-7-(3-morpholinopropoxy)quinazoline

Using an analogous procedure to that described in Example 26,4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline was reacted withN-(3-amino-4-methylphenyl)-2-morpholinopyridine-4-carboxamide to givethe title compound in 58% yield; NMR: 1.96 (m, 2H), 2.13 (s, 3H), 3.29(m, 4H), 3.5 (m, 4H), 3.59 (m, 4H), 3.69 (m, 4H), 3.92 (s, 3H), 4.18 (m,2H), 7.08 (m, 1H), 7.13 (s, 1H), 7.22 (s, 1H), 7.28 (m, 1H), 7.58 (m,1H), 7.75 (m, 1H), 7.81 (s, 1H), 8.27 (m, 2H), 9.39 (s, 1H), 10.29 (s,1H); m/s: M+H⁺ 614.

Example 767-Fluoro-4-[2-methyl-5-(2-morpholinopyridine-4-carboxamido)anilino]quinazolinedihydrochloride

Using an analogous procedure to that described in Example 26 except that2 equivalents of the 1M solution of hydrogen chloride in diethyl etherwere used, 4-chloro-7-chloroquinazoline (Chemical Abstracts, volume 122,no. 31545; European Patent Application No. 0602851) was reacted withN-(3-amino-4-methylphenyl)-2-morpholinopyridine-4-carboxamide. Aftercooling the reaction mixture to room temperature, the precipitated solidwas isolated and washed in turn with isohexane and diethyl ether toyield the title compound in 41% yield; m/s: M+H⁺ 459.

Example 776-Methoxy-7-(3-methylsulphonylpropoxy)-4-[2-methyl-5-(2-morpholinopyridine-4-carboxamido)anilino]quinazoline

A mixture of7-hydroxy-6-methoxy-4-[2-methyl-5-(2-morpholinopyridine-4-carboxamido)anilino]quinazoline(250 mg), 3-methylsulphonylpropyl) 4-toluenesulphonate (150 mg), cesiumcarbonate (501 mg) and N,N-dimethylacetamide (5 ml) was stirred andheated to 100° C. for 1 hour. After cooling the reaction mixture toambient temperature, water was added and the precipitated solid wasisolated and dried under vacuum. The material so obtained was purifiedby column chromatography on silica using a 10:1 mixture of methylenechloride and methanol as eluent. There was thus obtained the titlecompound as a solid (38 mg); NMR: 2.14 (s, 3H), 2.13 (m, 2H), 3.02 (s,3H), 3.24 (m, 2H), 3.49 (m, 4H), 3.68 (m, 4H), 3.93 (s, 3H), 4.29 (t,2H), 7.08 (d, 1H), 7.16 (s, 1H), 7.21 (s, 1H), 7.27 (d, 1H), 7.58 (d,1H), 7.76 (s, 1H), 7.83 (s, 1H), 8.25 (d, 1H), 8.27 (s, 1H), 9.4 (s,1H), 10.28 (s, 1H); m/s: M+H⁺ 607.

The7-hydroxy-6-methoxy-4-[2-methyl-5-(2-morpholinopyridine-4-carboxamido)anilino]quinazolineused as a starting material was prepared as follows:

A mixture of 7-benzyloxy-4-chloro-6-methoxyquinazoline hydrochloride(2.95 g), N-(3-amino-4-methylphenyl)-2-morpholinopyridine-4-carboxamide(2.73 g) and isopropanol (60 ml) was stirred and heated to 90° C. for 3hours. The reaction mixture was cooled to ambient temperature and theprecipitated solid was isolated and washed in turn with isopropanol andisohexane. There was thus obtained7-benzyloxy-6-methoxy-4-[2-methyl-5-(2-morpholinopyridine-4-carboxamido)anilino]quinazolinedihydrochloride as a solid which was used in the next reaction withoutfurther purification; NMR: 2.17 (s, 3H), 3.65 (m, 4H), 3.74 (m, 4H),4.01 (s, 3H), 5.33 (s, 2H), 7.2 (d, 1H), 7.35-7.53 (m, 7H), 7.61 (s,1H), 7.71 (d, 1H), 7.87 (s, 1H), 8.19 (d, 1H), 8.38 (s, 1H), 8.69 (s,1H), 10.81 (s, 1H), 11.61 (s, 1H); m/s: M+H⁺ 577.

A mixture of7-benzyloxy-6-methoxy-4-[2-methyl-5-(2-morpholinopyridine-4-carboxamido)anilino]quinazolinedihydrochloride (4.45 g) and trifluoroacetic acid (20 ml) was stirredand heated to reflux for 90 minutes. The mixture was cooled to ambienttemperature and evaporated. A mixture of a dilute aqueous sodiumbicarbonate solution and methylene chloride was added to the residue andthe resultant mixture was stirred for 30 minutes at ambient temperature.The precipitated solid was collected, washed with water and dried undervacuum at 60° C. to give7-hydroxy-6-methoxy-4-[2-methyl-5-(2-morpholinopyridine-4-carboxamido)anilino]quinazoline(3.67 g; NMR: 2.17 (s, 3H), 3.52 (t, 4H), 3.71 (t, 4H), 3.98 (s, 3H),7.09 (d, 1H), 7.19 (s, 1H), 7.23 (s, 1H), 7.37 (d, 1H), 7.6 (d, 1H),7.84 (s, 1H), 8.05 (s, 1H), 8.25 (d, 1H), 8.66 (s, 1H), 10.42 (s, 1H),11.06 (s, 1H); m/s: M+H⁺ 487.

The 3-methylsulphonylpropyl 4-toluenesulphonate used as a startingmaterial was prepared as follows:

A solution of 3-methylthiopropan-1-ol (9.0 g) in methylene chloride (135ml) was cooled to 5° C. Triethylamine (13.1 ml) was added followed by4-tosyl chloride (17.73 g). The mixture was stirred for 18 hours. Thereaction mixture was washed with a saturated aqueous sodium bicarbonatesolution, dried over magnesium sulphate and evaporated. The residue waspurified by column chromatography on silica using a 10:1 mixture ofisohexane and ethyl acetate as eluent. There was thus obtained3-methylthiopropyl 4-toluenesulphonate (9.0 g, 45%); NMR: 1.8 (m, 2H),1.96 (s, 3H), 2.4 (t, 2H), 2.41 (s, 3H), 4.08 (t, 2H), 7.47 (d, 2H),7.78 (d, 2H); m/s: M+H⁺ 261.

A solution of potassium peroxymonosulphate (oxone®; 33 g) in water (250ml) was added to a solution of 3-methylthiopropyl 4-toluenesulphonate(14.29 g) in methanol (1.5 L). The resulting mixture was stirred for 18hours, filtered and evaporated. The residue was dissolved in ethylacetate and the solution was washed with brine, dried over magnesiumsulphate and evaporated. There was thus obtained 3-methylsulphonylpropyl4-toluenesulphonate as a solid (10.22 g, 64%); NMR: 2.01 (m, 2H), 2.43(s, 3H), 2.95 (s, 3H), 3.1 (t, 2H), 4.13 (t, 2H), 7.47 (d, 2H), 7.78 (d,2H); m/s: M+NH₄ ⁺ 310.

Examples 78-81

Using an analogous procedure to that described in Example 1, theappropriate acyl chloride was reacted with the appropriate aniline togive, unless otherwise stated in the appropriate footnote, thehydrochloride salt of each compound described in the following table.

Example No. R² R³ R⁴ Note 78 Me H 3-trifluoromethylphenyl a) 79 H H2-thienyl b) 80 Me H cyclopropyl c) 81 Me H methoxymethyl d) Notes a)The product gave the following data: NMR: 2.2(s, 3H), 3.98(s, 6H),7.32(m, 2H), 7.64(d, 1H), 7.77(m, 1H), 7.84(s, 1H), 7.91(d, 1H), 8.08(s,1H), 8.27(m, 2H), 8.73(s, 1H), 10.32(broad s, 1H); Mass: M+H⁺ 483. b)The product gave the following data: NMR: 3.94(s, 3H), 3.97(s, 3H),7.18(s, 1H), 7.22(m, 1H), 7.34(m, 1H), 7.46(d, 1H), 7.56(d, 1H), 7.85(d,1H), 7.88(s, 1H), 8.04(d, 1H), 8.2(m, 1H), 8.46(s, 1H), 9.49(s, 1H),10.25(s, 1H); Mass: M+H⁺ 407. c) The product gave the following data:NMR: 0.76(m, 4H), 2.14(s, 3H), 2.49(m, 1H), 3.97(s, 6H), 7.22(m, 2H),7.4(d, 1H), 7.65(s, 1H), 7.96(s, 1H), 8.43(s, 1H), 9.92(s, 1H); Mass:M+H⁺ 379. d) The product gave the following data: NMR: 2.15(s, 3H),2.49(m, 2H), 3.39(s, 3H), 3.98(s, 6H), 7.27(d, 1H), 7.29(s, 1H), 7.48(d,1H), 7.71(s, 1H), 8.04(s, 1H), 8.61(s, 1H), 9.62(s, 1H); Mass: M+H⁺ 383.

Example 824-[4-Fluoro-3-(ethoxycarbonylamino)anilino]-6,7-dimethoxyquinazoline

Ethyl chloroformate (0.058 ml) was added to a suspension of4-(3-amino-4-fluoroanilino)-6,7-dimethoxyquinazoline (159 mg) andtriethylamine (0.14 ml) in dry methylene chloride (3.5 ml) and theresulting mixture was stirred at ambient temperature for 18 hours.Methylene chloride (100 ml) was added and the mixture was washed withwater and brine, dried over magnesium sulphate, filtered and evaporatedto dryness. The residue was purified by silica column chromatography,eluting with 2% methanol in methylene chloride to yield the titlecompound as a solid (38 mg, 19%); NMR: 1.23 (t, 3H), 3.91 (s, 3H), 3.94(s, 3H), 4.12 (m, 2H), 7.16 (s, 1H), 7.21 (m, 1H), 7.57 (m, 1H), 7.83(s, 1H), 8.0 (m, 1H), 8.42 (s, 1H), 9.28 (s, 1H), 9.49 (s, 1H); m/s:M+H⁺ 387.

Example 83

4-[5-(4Cyanobenzamido)anilino]-6-methoxy-7-(3-morpholinopropoxy)quinazoline

Using an analogous procedure to that described in Example 26,4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline was reacted withN-(3-aminophenyl)-4-cyanobenzamide. The material so obtained waspurified by column chromatography eluting with 85:10:5 methylenechloride/methanol/isopropylamine. The material so obtained wastriturated under diethyl ether to give the title compound in 48% yield;NMR: 2.1 (m, 2H), 3.35-3.45 (m, 4H), 3.7-3.8 (m, 8H), 3.98 (s, 3H), 4.22(m, 2H), 7.2 (s, 1H), 7.38 (m, 1H), 7.51 (m, 1H), 7.58 (m, 1H), 7.93 (s,1H), 8.04 (d, 2H), 8.13 (d, 2H), 8.31 (s, 1H), 8.46 (s, 1H), 9.59 (s,1H); Mass: M+H⁺ 539.

Example 846,7-dimethoxy-4-[3-(2-morpholinopyridine-4-carboxamido)anilino]quinazoline

Using an analogous procedure to that described in Example 26,4-chloro-6,7-dimethoxyquinazoline was reacted withN-(3-aminophenyl)-2-morpholinopyridine-4-carboxamide. The material soobtained was purified by column chromatography eluting with 96:3:1methylene chloride/methanol/saturated aqueous ammonium hydroxide. Thematerial so obtained was triturated under methylene chloride to give thetitle compound in 33% yield; NMR: 3.51 (m, 4H), 3.71 (m, 4H), 3.93 (s,3H), 3.96 (s, 3H), 7.11 (d, 1H), 7.18 (s, 1H), 7.24 (s, 1H), 7.35 (m.1H), 7.44 (d, 1H), 7.57 (d, 1H), 7.86 (s, 1H), 8.23 (s, 1H), 8.29 (d,1H), 8.46 (s, 1H), 9.49 (s, 1H), 10.34 (s, 1H); Mass: M+H⁺ 487.

The N-(3-aminophenyl)-2-morpholinopyridine-4-carboxamide used as astarting material was prepared as follows:

Triethylamine (6.7 ml) was added to a stirred mixture of 3-nitroaniline(3 g), 2-chloropyridine-4-carbonyl chloride (4.6 g) and methylenechloride (50 ml) and the resultant mixture was stirred at ambienttemperature for 40 hours. The mixture was evaporated and the residue wastriturated under water. The solid so obtained was isolated, washed witha saturated aqueous sodium bicarbonate solution and dried under vacuumat 55° C. There was thus obtained2-chloro-N-(3-nitrophenyl)pyridine-4-carboxamide (6.03 g); NMR: (DMSOd₆)7.68 (t, 1H), 7.88 (t, 1H), 7.99 (m, 2H), 8.16 (d, 1H), 8.63 (d, 1H),8.73 (t, 1H), 10.95 (broad s, 1H); Mass: M+H⁺ 278.

A mixture of the pyridine-4-carboxamide so produced and morpholine (100ml) was stirred and heated to 130° C. for 3.5 hours and to 150° C. for 2hours. The mixture was poured into water (250 ml) and stirred for 10minutes. The resultant solid was isolated, washed in turn with water andwith isohexane and dried under vacuum at 55° C. There was thus obtainedN-(3-nitrophenyl)-2-morpholinopyridine-4-carboxamide (6.8 g); NMR:(DMSOd₆) 3.52 (t, 4H), 3.71 (t, 4H), 7.12 (d, 1H), 7.25 (s, 1H), 7.66(t, 1H), 7.97 (d, 1H), 8.15 (d, 1H), 8.29 (d, 1H), 8.73 (t, 1H), 10.72(broad s, 1H); Mass: M+H⁺ 329.

A mixture of the material so obtained, 10% palladium-on-carbon catalyst(0.68 g), ammonium formate (13 g) and methanol (150 ml) was stirred andheated to reflux for 2 hours. The reaction mixture was filtered throughdiatomaceous earth. The filtrate was evaporated and the residue wastriturated under water. The resultant solid was isolated, washed in turnwith water and with isohexane and dried under vacuum at 55° C. There wasthus obtained N-(3-aminophenyl)-2-morpholinopyridine-4-carboxamide (5.38g); NMR: (DMSOd₆) 3.51 (t, 4H), 3.71 (t, 4H), 5.07 (broad s, 2H), 6.33(d, 1H), 6.81 (d, 1H), 6.95 (t, 1H), 7.05 (m, 2H), 7.2 (s, 1H), 8.24 (d,1H), 9.96 (broad s, 1H); Mass: M+H⁺ 299.

Example 856-Methoxy-7-[2-(1,2,3-triazol-1-yl)ethoxy]-4-[2-methyl-5-(2-morpholinopyridine-4-carboxamido)anilino]quinazoline

A mixture of7-hydroxy-6-methoxy-4-[2-methyl-5-(2-morpholinopyridine-4-carboxamido)anilino]quinazoline(184 mg), 2-(1,2,3-triazol-1-yl)ethyl 4-toluenesulphonate (101 mg),cesium carbonate (370 mg) and N,N-dimethylacetamide (4 ml) was stirredand heated to 100° C. for 1 hour. After cooling the reaction mixture toambient temperature, the reaction mixture was partitioned between waterand methylene chloride. The organic phase was dried with brine andsodium sulphate and evaporated. The material so obtained was purified bycolumn chromatography on silica using a 10:1 mixture of methylenechloride and methanol as eluent. There was thus obtained the titlecompound as a solid (47 mg); NMR: 2.14 (s, 3H), 3.51 (t, 4H), 3.72 (t,4H), 3.91 (s, 3H), 4.59 (t, 2H), 4.87 (t, 2H), 7.09 (d, 1H), 7.2 (s,1H), 7.22 (d, 1H), 7.27 (d, 1H), 7.58 (m, 1H), 7.74 (s, 2H), 7.83 (s,1H), 8.18 (s, 1H), 8.24 (d, 1H), 8.26 (s, 1H), 9.39 (s, 1H), 10.28 (s,1H); m/s: M+H⁺ 582.

The 2-(1,2,3-triazol-1-yl)ethyl 4-toluenesulphonate used as a startingmaterial was prepared as follows:

Sodium metal (1.75 g) was added portionwise to anhydrous ethanol (100ml) and the resultant mixture was stirred at ambient temperature for 30minutes. 1,2,3-Triazole (5 g) and bromoethanol (5.67 ml) were added inturn and the resultant mixture was stirred and heated to reflux for 5hours. The mixture was cooled to ambient temperature and filtered. Thefiltrate was diluted with ethyl acetate and the resultant mixture wasfiltered. The filtrate was evaporated and the residue was purified bycolumn chromatography on silica using a 3:1 mixture of hexane and ethylacetate as eluent. There was thus obtained 2-(1,2,3-triazol-1-yl)ethanol(1.95 g); NMR: 3.76 (m, 2H), 4.4 (t, 2H), 4.97 (t, 1H), 7.67 (s, 1H),8.04 (s, 1H).

Triethylamine (0.68 ml) and 4-toluenesulphonyl chloride (0.19 g) wereadded in turn to a solution of 2-(1,2,3-triazol-1-yl)ethanol (0.113 g)in methylene chloride (15 ml) which had been cooled to 5° C. Theresultant mixture was stirred at ambient temperature for 2 hours. Themixture was evaporated and the residue was purified by columnchromatography on silica using increasingly polar mixtures of hexane andethyl acetate as eluent. There was thus obtained the required startingmaterial. (0.85 g); NMR: 2.38 (s, 3H), 4.39 (t, 2H), 4.66 (t, 2H), 7.41(d, 2H), 7.43 (s, 1H), 7.62 (s, 1H), 7.65 (d, 2H), 8.03 (s, 1H).

Example 86 Pharmaceutical Compositions

The following illustrate representative pharmaceutical dosage forms ofthe invention as defined herein (the active ingredient being termed“Compound X”), for therapeutic or prophylactic use in humans:

(a) Tablet I mg/tablet Compound X 100 Lactose Ph. Eur 182.75Croscarmellose sodium 12.0 Maize starch paste (5% w/v paste) 2.25Magnesium stearate 3.0 (b) Tablet II mg/tablet Compound X 50 Lactose Ph.Eur 223.75 Croscarmellose sodium 6.0 Maize starch 15.0Polyvinylpyrrolidone (5% w/v paste) 2.25 Magnesium stearate 3.0 (c)Tablet III mg/tablet Compound X 1.0 Lactose Ph. Eur 93.25 Croscarmellosesodium 4.0 Maize starch paste (5% w/v paste) 0.75 Magnesium stearate 1.0(d) Capsule mg/capsule Compound X 10 Lactose Ph. Eur 488.5 Magnesium 1.5(e) Injection I (50 mg/ml) Compound X 5.0% w/v 1 M Sodium hydroxidesolution 15.0% v/v 0.1 M Hydrochloric acid (to adjust pH to 7.6)Polyethylene glycol 400 4.5% w/v Water for injection to 100% (f)Injection II (10 mg/ml) Compound X 1.0% w/v Sodium phosphate BP 3.6% w/v0.1 M Sodium hydroxide solution 15.0% v/v Water for injection to 100%(g) Injection III (1 mg/ml, buffered to pH6) Compound X 0.1% w/v Sodiumphosphate BP 2.26% w/v Citric acid 0.38% w/v Polyethylene glycol 4003.5% w/v Water for injection to 100% (h) Aerosol I mg/ml Compound X 10.0Sorbitan trioleate 13.5 Trichlorofluoromethane 910.0Dichlorodifluoromethane 490.0 (i) Aerosol II mg/ml Compound X 0.2Sorbitan trioleate 0.27 Trichlorofluoromethane 70.0Dichlorodifluoromethane 280.0 Dichlorotetrafluoroethane 1094.0 (j)Aerosol III mg/ml Compound X 2.5 Sorbitan trioleate 3.38Trichlorofluoromethane 67.5 Dichlorodifluoromethane 1086.0Dichlorotetrafluoroethane 191.6 (k) Aerosol IV mg/ml Compound X 2.5 Soyalecithin 2.7 Trichlorofluoromethane 67.5 Dichlorodifluoromethane 1086.0Dichlorotetrafluoroethane 191.6 (l) Ointment ml Compound X 40 mg Ethanol300 μl Water 300 μl 1-Dodecylazacycloheptan-2-one 50 μl Propylene glycolto 1 ml Note The above formulations may be obtained by conventionalprocedures well known in the pharmaceutical art. The tablets (a)-(c) maybe enteric coated by conventional means, for example to provide acoating of cellulose acetate phthalate. The aerosol formulations (h)-(k)may be used in conjunction with standard, metered dose aerosoldispensers, and the suspending agents sorbitan trioleate and soyalecithin may be replaced by an alternative # suspending agent such assorbitan monooleate, sorbitan sesquioleate, polysorbate 80, polyglycerololeate or oleic acid.

What is claimed is:
 1. An amide derivative of the Formula (I):

wherein: G is N; R¹ is hydroxy, halo, trifluoromethyl, cyano, mercapto,nitro, amino, carboxy, carbamoyl, formyl, sulphamoyl, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy, —O—(C₁₋₃alkyl)—O—,C₁₋₆alkylS(O)_(n)— (wherein n is 0-2), N—C₁₋₆alkylamino,N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkoxycarbonyl, N—C₁₋₆alkylcarbamoyl,N,N—(C₁₋₆alkyl)₂carbamoyl, C₂₋₆alkanoyl, C₁₋₆alkanoyloxy,C₁₋₆alkanoylamino, N—C₁₋₆alkylsulphamoyl, N,N—(C₁₋₆alkyl)₂sulphamoyl,C₁₋₆alkylsulphonylamino, C₁₋₆alkylsulphonyl—N—(C₁₋₆alkyl)amino, or R¹ isof the Formula (IA): A—(CH₂)_(p)—B—  (IA) wherein A is halo, hydroxy,C₁₋₆alkoxy, C₁₋₆alkylS(O)_(n)— (wherein n is 0-2), cyano, amino,N—C₁₋₆alkylamino, N,N—(C₁₋₆alkyl)₂amino, carboxy, C₁₋₆alkoxycarbonyl,carbamoyl, N—C₁₋₆alkylcarbamoyl or N,N—(C₁₋₆alkyl)₂carbamoyl, p is 1-6,and B is a bond, oxy, imino, N—(C₁₋₆alkyl)imino or —C(O)NH—, with theproviso that p is 2 or more unless B is a bond or —C(O)NH—, or R¹ is ofthe Formula (IB): D—E—  (IB) wherein D is aryl, heteroaryl orheterocyclyl and E is a bond, C₁₋₆alkylene, C₁₋₆alkyleneoxy, oxy, imino,N—(C₁₋₆alkyl)imino, C₁₋₆alkyleneimino, N—(C₁₋₆alkyl)-C₁₋₆alkyleneimino,C₁₋₆alkyleneoxy-C₁₋₆alkylene, C₁₋₆alkyleneimino-C₁₋₆alkylene,N—(C₁₋₆alkyl)-C₁₋₆alkyleneimino-C₁₋₆alkylene, —C(O)NH—, —SO₂NH—, —NHSO₂—or C₂₋₆alkanoylimino, and any aryl, heteroaryl or heterocyclyl group ina R¹ group may be optionally substituted with one or more groupsselected from hydroxy, halo, C₁₋₆alkyl, C₁₋₆alkoxy, carboxy,C₁₋₆alkoxycarbonyl, carbamoyl, N—C₁₋₆alkylcarbamoyl,N,N—(C₁₋₆alkyl)₂carbamoyl, C₂₋₆alkanoyl, amino, N—C₁₋₆alkylamino andN,N—(C₁₋₆alkyl)₂amino, and any heterocyclyl group in a R¹ group may beoptionally subsituted with one or two oxo or thioxo subsituents, and anyof the R¹ groups defined hereinbefore which comprises a CH₂ group whichis attached to 2 carbon atoms or a CH₃ group which is attached to acarbon atom may optionally bear on each said CH₂ or CH₃ group asubstituent selected from hydroxy, amino, C₁₋₆alkoxy, N—C₁₋₆alkylamino,N,N—(C₁₋₆alkyl)₂amino and heterocyclyl; R² is hydrogen, halo, C₁₋₆alkyl,C₂₋₆alkenyl or C₂₋₆alkynyl; R³ is hydrogen, halo, C₁₋₆alkyl, C₂₋₆alkenylor C₂₋₆alkynyl; R⁴ is hydrogen, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy, amino,N—C₁₋₆alkylamino, N,N—(C₁₋₆alkyl)₂amino, hydroxyC₂₋₆alkoxy,C₁₋₆alkoxyC₂₋₆alkoxy, aminoC₂₋₆alkoxy, N—C₁₋₆alkylaminoC₂₋₆alkoxy,N,N—(C₁₋₆alkyl)₂aminoC₂₋₆alkoxy or C₃₋₇cycloalkyl, or R⁴ is of theFormula (IC): —K—J  (IC) wherein J is aryl, heteroaryl or heterocyclyland K is a bond, oxy, imino, N—(C₁₋₆alkyl)imino, oxy C₁₋₆alkylene,iminoC₁₋₆alkylene, N—(C₁₋₆alkyl)iminoC₁₋₆alkylene, —NHC(O)—, —SO₂NH—,—NHSO₂— or —NHC(O)—C₁₋₆alkylene-, and any aryl, heteroaryl orheterocyclyl group in a R⁴ group may be optionally substituted by one ormore groups selected from hydroxy, halo, trifluoromethyl, cyano,mercapto, nitro, amino, carboxy, carbamoyl, formyl, sulphamoyl,C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy, —O—(C₁₋₃alkyl)—O—,C₁₋₆alkylS(O)_(n)— (wherein n is 0-2), N—C₁₋₆alkylamino,N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkoxycarbonyl, N—C₁₋₆alkylcarbamoyl,N,N—(C₁₋₆alkyl)₂carbamoyl, C₂₋₆alkanoyl, C₁₋₆alkanoyloxy,C₁₋₆alkanoylamino, N—C₁₋₆alkylsulphamoyl, N,N—(C₁₋₆alkyl)₂sulphamoyl,C₁₋₆alkylsulphonylamino and C₁₋₆alkylsulphonyl-N—(C₁₋₆alkyl)amino, orany aryl, heteroaryl or heterocyclyl group in a R⁴ group may beoptionally substituted with one or more groups of the Formula (IA′):—B¹—(CH₂)_(p)—A¹  (IA′) wherein A¹ is halo, hydroxy, C₁₋₆alkoxy, cyano,amino, N—C₁₋₆alkylamino, N,N—(C₁₋₆alkyl)₂amino, carboxy,C₁₋₆alkoxycarbonyl, carbamoyl, N—C₁₋₆alkylcarbamoyl orN,N—(C₁₋₆alkyl)₂carbamoyl, p is 1-6, and B¹ is a bond, oxy, imino,N—(C₁₋₆alkyl)imino or —NHC(O)—, with the proviso that p is 2 or moreunless B¹ is a bond or —NHC(O)—; or any aryl, heteroaryl or heterocyclylgroup in a R⁴ group may be optionally substituted with one or moregroups of the Formula (IB′): —E¹—D¹  (IB′) wherein D¹ is aryl,heteroaryl or heterocyclyl and E¹ is a bond, C₁₋₆alkylene,oxyC₁₋₆alkylene, oxy, imino, N—(C₁₋₆alkyl)imino, iminoC₁₋₆alkylene,N—(C₁₋₆alkyl)iminoC, ₆alkylene, C₁₋₆alkylene-oxyC₁₋₆alkylene,C₁₋₆alkylene-iminoC₁₋₆alkylene,C₁₋₆alkylene-N—(C₁₋₆alkyl)-iminoC₁₋₆alkylene, —NHC(O)—, —NHSO₂—, —SO₂NH—or —NHC(O)—C₁₋₆alkylene—, and any aryl, heteroaryl or heterocyclyl groupin a substituent on R⁴ may be optionally substituted with one or moregroups selected from hydroxy, halo, C₁₋₆alkyl, C₁₋₆alkoxy, carboxy,C₁₋₆alkoxycarbonyl, carbamoyl, N—C₁₋₆alkylcarbamoyl,N,N—(C₁₋₆alkyl)₂carbamoyl, C₂₋₆alkanoyl, amino, N—C₁₋₆alkylamino andN,N—(C₁₋₆alkyl)₂amino, and any C₃₋₇cycloalkyl or heterocyclyl group in aR⁴ group may be optionally substituted with one or two oxo or thioxosubstituents, and any of the R⁴ groups defined hereinbefore whichcomprises a CH₂ group which is attached to 2 carbon atoms or a CH₃ groupwhich is attached to a carbon atom may optionally bear on each said CH₂or CH₃ group a substituent selected from hydroxy, amino, C₁₋₆alkoxy,N—C₁₋₆alkylamino, N,N—(C₁₋₆alkyl)₂amino and heterocyclyl; R⁵ ishydrogen, halo, trifluoromethyl, cyano, nitro, amino, hydroxy,C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy, N—C₁₋₆akylamino orN,N—(C₁₋₆alkyl)₂amino; m is 1, 2 or 3; and q is 0, 1, 2, 3 or 4; or apharmaceutically acceptable salt or an in vivo cleavable ester thereof;with the proviso that: 4-(3-acetamidoanilino)-6,7-dimethoxyquinazoline;and 4-(3-benzamidoanilino)-6,7-dimethoxyquinazoline are excluded.
 2. Anamide derivative of the Formula (I) according to claim 1 wherein R¹ ishydroxy, halo, C₁₋₆alkoxy, N,N—(C₁₋₆alkyl)₂aminoC₁₋₆alkyl,N,N—(C₁₋₆alkyl)₂carbarnoylC₁₋₆alkoxy, N,N-(C₁₋₆alkyl)₂aminoC₁₋₆alkoxy,C₁₋₆alkyS(O)₂—C₁₋₆alkoxy,N,N—(C₁₋₆alkyl)₂amino-N—(C₁₋₆alkyl)C₁₋₆alkylamino,N,N—(C₁₋₆alkyl)₂aminoC₁₋₆alkylaminoC₁₋₆alkyl, heterocyclylC₁₋₆alkyl,heterocyclylC₁₋₆alkoxy, heterocyclyloxy,heterocyclylC₁₋₆alkylaminoC₁₋₆alkyl or heteroarylC₁₋₆alkoxy.
 3. An amidederivative of the Formula (I) according to claim 1 wherein R² isC₁₋₄alkyl or halo when R³ is hydrogen.
 4. An amide derivative of theFormula (I) according to claim 1 wherein R³ is C₁₋₄alkyl or halo when R²is hydrogen.
 5. An amide derivative of the Formula (I) according toclaim 1 wherein R⁴ is hydrogen or C₁₋₆alkoxy or R⁴ is aryl or heteroaryloptionally substituted by one or more groups selected from halo, cyano,C₁₋₆alkyl, C₁₋₆alkoxy, N,N—(C₁₋₆alkyl)₂amino or heterocyclyl.
 6. Anamide derivative of the Formula (I) according to claim 1 wherein R¹ ishydroxy, halo, C₁₋₆alkoxy, N,N—(C₁₋₆alkyl)₂aminoC₁₋₆alkyl,N,N—(C₁₋₆alkyl)₂carbamoylC₁₋₆alkoxy, N,N—(C₁₋₆alkyl)₂aminoC₁₋₆alkoxy,C₁₋₆alkylS(O)₂—C₁₋₆alkoxy,N,N—(C₁₋₆alkyl)₂amino-N—(C₁₋₆alkyl)C₁₋₆alkylamino,N,N—(C₁₋₆alkyl)₂aminoC₁₋₆alkylaminoC₁₋₆alkyl, heterocyclylC₁₋₆alkyl,heterocyclyl-C₁₋₆alkoxy, heterocyclyloxy,heterocyclylC₁₋₆alkylaminoC₁₋₆alkyl or heteroarylC₁₋₆alkoxy; R² ishydrogen, C₁₋₆alkyl or halo; R³ is hydrogen, C₁₋₆alkyl or halo; R⁴ ishydrogen or C₁₋₆alkoxy or R⁴is aryl or heteroaryl optionally substitutedby one or more groups selected from halo, cyano, C₁₋₆alkyl, C₁₋₆alkoxy,N,N—(C₁₋₆alkyl)₂amino or heterocyclyl; R⁵ is hydrogen; G is N; m is 1, 2or 3; and q is 0 or 1; or a pharmaceutically acceptable salt, or an invivo cleavable ester thereof.
 7. An amide derivative of the Formula (I)according to claim 1 wherein R¹ is C₁₋₆alkoxy, morpholinylC₁₋₆alkoxy,pyrrolidinylC₁₋₆alkoxy or pyridylC₁₋₆alkoxy; R² is hydrogen, C₁₋₆alkylor halo; R³ is hydrogen, C₁₋₆alkyl or halo; R⁴ is hydrogen or C₁₋₆alkoxyor R⁴ is aryl or heteroaryl optionally substituted by one or more groupsselected from halo, cyano, C₁₋₆alkyl, C₁₋₆alkoxy, N,N—(C₁₋₆alkyl)₂amino,piperidinyl, morpholino or piperazinyl; R⁵ is hydrogen; G is N; m is 2or 3; and q is 0 or 1; or a pharmaceutically acceptable salt, or an invivo cleavable ester thereof.
 8. An amide derivative of the Formula (I)according to claim 1 wherein R¹ is methoxy, 2-dimethylaminoethoxy,2-diethylaminoethoxy, 2-diisopropylaminoethoxy, 3-dimethylaminopropoxy,3-diethylaminopropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy,2-piperidinoethoxy, N-methylpiperidin-2-ylmethoxy,N-methylpiperidin-3-ylmethoxy, 2-pyrrolidin-1-ylethoxy,2-(N-methylpyrrolidin-2-yl)ethoxy, N-methyl-5-oxopyrrolidin-2-ylmethoxy,3-pyrrolidin-1-ylpropoxy, 2-(2-oxoimidazolidin-1-yl)ethoxy,2-(4-methylpiperazin-1-yl)ethoxy or 3-pyrid-3-ylpropoxy; R² is hydrogen.methyl, fluoro or chloro; R³ is hydrogen, methyl, fluoro or chloro; R⁴is pyridyl optionally substituted by a N,N-dimethylamino,N,N-diethylamino, pyrrolidin-1-yl, piperidino or morpholino group. R⁵ ishydrogen; G is N; m is 1, 2 or 3; and q is 0; or a pharmaceuticallyacceptable salt, or an in vivo cleavable ester thereof.
 9. An amidederivative of the Formula (I) according to claim 1 selected from:4-(3-benzamido-4-fluoroanilino)-6,7-dimethoxyquinazoline,6-(2-diisopropylaminoethoxy)-7-methoxy-4-[2-methyl-5-(2-morpholinopyridine-4-carboxamido)anilino]quinazoline,6-(2-dimethylaminoethoxy)-7-methoxy-4-[2-methyl-5-(2-morpholinopyridine-4-carboxamido)anilino]quinazolineand6-(3-pyrrolidin-1-ylpropoxy)-7-methoxy-4-[2-methyl-5-(2-morpholinopyridine-4-carboxamido)anilino]quinazoline;or a pharmaceutically acceptable salt or an in vivo cleavable esterthereof.
 10. A process for preparing an amide derivative of the Formula(I), or a pharmaceutically acceptable salt or an in vivo cleavable esterthereof, as claimed in claim 1 which comprises: a) reacting an anilineof the Formula (II):

 wherein variable groups are as defined in claim 1 and any functionalgroup is protected if necessary, with an acyl compound of the Formula(III):

 wherein variable groups are as defined in claim 1, L is a displaceablegroup and any functional group is protected if necessary; b) reacting anactivated heteroaryl of the Formula (IV):

 wherein variable groups are as defined in claim 1, L is a displaceablegroup and any functional group is protected if necessary, with ananiline of the Formula (V):

 wherein variable groups are as defined in claim 1 and any functionalgroup is protected if necessary; or c) for the preparation of a compoundof the Formula (I) wherein R¹ or a substituent on R⁴ is C₁₋₆alkoxy orsubstituted C₁₋₆alkoxy, C₁₋₆alkylS—, N—C₁₋₆alkylamino,N,N—(C₁₋₆alkyl)₂amino or substituted C₁₋₆alkylamino, the alkylation,conveniently in the presence of a suitable base, of an amide derivativeof the Formula (I) wherein R¹ or a substituent on R⁴ is hydroxy,mercapto or amino as appropriate; and thereafter if necessary: i)removing any protecting groups; and ii) forming a pharmaceuticallyacceptable salt or in vivo cleavable ester.
 11. A pharmaceuticalcomposition which comprises an amide derivative of the Formula (I), or apharmaceutically acceptable salt or an in vivo cleavable ester thereof,as claimed in claim 1 in association with a pharmaceutically acceptablediluent or carrier.
 12. A method of treating a disease or medicalcondition mediated by a cytokine which comprises administering to awarm-blooded animal an effective amount of a compound of Formula (I), ora pharmaceutically-acceptable salt or in vivo cleavable ester thereof,according to claim 1.